10-K
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10-K
10-K
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UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 10-K
(Mark One)
For the fiscal year ended December 31, 2020
OR
For the transition period
from to
Commission File Number 001-39988
Bolt Biotherapeutics, Inc.
(Exact name of Registrant as specified in its Charter)
900 Chesapeake Drive Redwood City, CA 94063
(Address of principal executive offices) (Zip Code)
Registrant’s telephone number, including area code:
(650) 665-9295
Securities registered pursuant to Section 12(b) of the Act:
Title of each class Trading Symbol(s) Name of each exchange on which registered
Common Stock, $0.00001 par value BOLT The Nasdaq Global Select Market
Securities registered pursuant to Section 12(g) of the Act: None
Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities
Act. YES ☐ NO ☒
Indicate by check mark if the Registrant is not required to
file reports pursuant to Section 13 or 15(d) of the Act. YES ☐ NO ☒
Indicate by check mark whether the Registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of
1934 during the preceding 12 months (or for such shorter period that the Registrant was required to file such reports), and (2) has been subject to such filing requirements for the past
90 days. YES ☐ NO ☒
Indicate by check mark whether the Registrant has
submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such
shorter period that the Registrant was required to submit such files). YES ☒ NO ☐
Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated
filer, smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☐
Non-accelerated filer ☒ Smaller reporting company ☒
Emerging growth company ☒
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period
for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☒
Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal
control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☐
Indicate by check mark whether the Registrant is a shell company (as defined in Rule 12b-2 of the Exchange
Act). YES ☐ NO ☒
The registrant did not have a public float on the last
business day of its most recently completed second fiscal quarter because there was no public market for the registrant’s common equity as of such date.
As of March 26, 2021, the registrant had 36,327,914 shares of common stock outstanding.
Table of Contents
Table of Contents
Page
PART I
Item 1. Business 2
Item 1A. Risk Factors 54
Item 1B. Unresolved Staff Comments 106
Item 2. Properties 106
Item 3. Legal Proceedings 106
Item 4. Mine Safety Disclosures 106
PART II
Item 6. Selected Financial Data 108
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 122
Item 8. Financial Statements and Supplementary Data 122
Item 9A. Controls and Procedures 122
Item 9B. Other Information 123
PART III
Item 10. Directors, Executive Officers and Corporate Governance 124
Item 11. Executive Compensation 130
Item 14. Principal Accounting Fees and Services 152
PART IV
Item 15. Exhibits, Financial Statement Schedules 154
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SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS
This Annual Report contains forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended (the
“Exchange Act”). All statements other than statements of historical facts contained in this Annual Report are forward-looking statements, including statements regarding:
• our beliefs regarding our industry;
• our ability to attract and retain key personnel;
These statements involve known and unknown risks, uncertainties and other important factors that may cause our
actual results, performance and achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements.
In some cases, you can identify forward-looking statements by terminology such as “may,” “will,” “should,” “could,”
“expects,” “intends,” “plans,” “anticipates,” “believes,” “estimates,” “predicts,” “potential,” “continue,” or the negative of these terms or other comparable
terminology. These forward-looking statements are only predictions. We have based these forward-looking statements largely on our current expectations and projections about future events and financial trends that we believe may affect our business,
financial condition and results of operations. These forward-looking statements speak only as of the date of this Annual Report on Form 10-K and are subject to a number of risks, uncertainties and assumptions,
including those described in Part I, Item 1A, “Risk Factors.” The events and circumstances reflected in our forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the
forward-looking statements. Moreover, we operate in an evolving environment. New risk factors and uncertainties may emerge from time to time, and it is not possible for management to predict all risk factors and uncertainties. Except as
required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise.
We have common law trademark rights in the unregistered marks “Bolt Biotherapeutics, Inc..,” “Boltbody,” and
the Bolt logo in certain jurisdictions. Solely for convenience, trademarks and tradenames referred to in this Annual Report appear without the ® and TM symbols, but those references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights or that the applicable owner will not
assert its rights, to these trademarks and tradenames.
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PART I
Item 1. Business.
Overview
We are a clinical-stage
immuno-oncology company developing tumor-targeted therapies that leverage the power of the innate and adaptive immune systems. Our proprietary Boltbody immune stimulating antibody conjugate (“ISAC”) approach uses immunostimulants to engage
and activate myeloid cells, including macrophages and dendritic cells, that directly kill tumor cells via phagocytosis and expose tumor neoantigens to the adaptive immune system. This leads to recruitment of cytotoxic T cells and additional
tumor-killing myeloid cells thereby converting immunologically “cold” tumors to “hot” tumors. We believe that this process leads to the development of systemic immunological memory with epitope spreading to neoantigens that is
critical to achieving a long-term anti-tumor response. Our lead product candidate BDC-1001 is a HER2 Boltbody ISAC comprised of a HER2-targeting biosimilar of trastuzumab conjugated to one of our proprietary
TLR7/8 agonists, for the treatment of patients with HER2-expressing solid tumors, including those with HER2-low tumors. We have demonstrated robust single agent anti-tumor activity in multiple preclinical
models, including elimination of large tumors (~500 mm3), as well as tumors that are refractory to trastuzumab or ado-trastuzumab emtansine. In our preclinical
safety studies, BDC-1001 was well tolerated and no adverse safety signals were observed. We believe these findings are encouraging for the therapeutic potential of
BDC-1001. We initiated a Phase 1/2 trial of BDC-1001 in the first quarter of 2020 for the treatment of patients with HER2-expressing solid tumors. We are currently in
the dose escalation portion of the trial and expect to move into Phase 2 dose expansions in key solid tumor indications with unmet medical need in 2021. We believe that our preliminary Phase 1/2 data provide us with clinical proof of concept for our
HER2 Boltbody ISAC approach. We are also advancing additional Boltbody ISAC product candidates targeting carcinoembryonic antigen (“CEA”) and PD-L1, both of which are currently in preclinical
development. We anticipate advancing our CEA Boltbody ISAC BDC-2034 into the clinic in 2022.
Our Boltbody ISAC approach is pioneering a new category of immunotherapies that combines the precision of antibody targeting with the strength
of the innate and adaptive immune systems by activating and recruiting myeloid cells, thereby re-programming the tumor microenvironment to invoke an adaptive immune response. Our Boltbody ISACs are delivered
systemically but act locally through a highly targeted approach that triggers a localized anti-tumor immune cascade through the following “Three-Factor Authentication” process designed to optimize safety and avoid systemic immune
stimulation.
During this “Three-Factor Authentication,” tumor-associated myeloid cells engulf the Boltbody ISAC-bound tumor cells, become armed
with tumor neoantigens, and migrate to the lymph nodes where they mediate the activation and rapid expansion of tumor-reactive T cells to eliminate tumor cells, including those without the initial target antigen. As a result, the patient’s
immune system determines which neoantigens are most important to eliminate the target tumors. We believe that this represents the development of systemic immunological memory with epitope spreading to neoantigens that will result in long-term
anti-tumor responses.
Unlike immuno-oncology approaches that solely seek to relieve immune suppression, Boltbody ISACs act by engaging
the immune system at multiple points in the cancer immunity cycle. Boltbody ISACs activate
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tumor-associated myeloid cells, leading to tumor phagocytosis and the presentation of tumor neoantigens to T cells that enable a productive anti-cancer response. The following key features
provide us with the opportunity to develop robust applications across various solid tumors designed to deliver effective and safe therapeutics that provide durable responses.
• Engaging the body’s innate and adaptive immune responses;
• Ability to target tumor antigens with less dense cell surface expression;
• Potential to benefit patients who have a defective adaptive immune response.
Our lead product candidate, BDC-1001, is currently in clinical development for the treatment of
patients with HER2-expressing solid tumors, including those with HER2-low tumors. We have designed BDC-1001 as a Boltbody ISAC comprised of a HER2-targeting biosimilar
trastuzumab conjugated to one of our proprietary TLR7/8 agonists to maximize the potential anti-tumor response. Through our preclinical studies in mice, we have demonstrated that systemic administration of HER2 Boltbody ISACs exhibited localized
immune activation that resulted in single agent activity that eliminated large (~500 mm3) tumors and generated immunological memory against cancers with epitope spreading. Furthermore, preclinical
data showed anti-tumor activity against established tumors resistant to trastuzumab and ado-trastuzumab emtansine, and immunological memory providing protection against tumor cells that no longer express the
HER2 antigen. Our observed preclinical anti-tumor response coupled with a lack of adverse safety signals in our non-human primate GLP toxicology studies leads us to believe that
BDC-1001 offers the potential for long-term and meaningful response for patients with HER2-expressing cancers, including HER2-low tumors. We initiated a Phase 1/2 trial
of BDC-1001 in the first quarter of 2020 for the treatment of patients with HER2-expressing solid tumors. We are currently in the dose escalation portion of the trial and expect to advance into Phase 2
dose expansions in 2021 in four clinically important and commercially compelling indications. We believe that our preliminary Phase 1/2 data provide us with clinical proof of concept for our HER2 Boltbody ISAC approach.
Our second program, BDC-2034, focuses on CEA, a well-known tumor antigen that is overexpressed in
various solid tumors with significant unmet medical need including, but not limited to, colorectal cancer, non-small cell lung cancer, pancreatic cancer and breast cancer. CEA is upregulated on the cell
surface of these cancers and displays minimal receptor-mediated internalization into the cancer cell. CEA allows us to target these cancers, some of which are immunologically “cold.” In our preclinical studies, we have observed promising
in vivo and in vitro activity with notable anti-tumor activity in xenograft models. We anticipate advancing BDC-2034 into the clinic in 2022.
Our third program, a PD-L1 Boltbody ISAC, focuses on the treatment of patients with tumors that are
nonresponsive or become refractory to immune checkpoint blockade. This encompasses more than 15 different tumor types impacting the lives of millions of patients yearly. Our PD-L1 program is a trifunctional
therapeutic with the following mechanism: 1) Antibody-dependent cellular phagocytosis of the tumor, 2) Myeloid activation and engagement of an adaptive T cell response, and 3)
PD-L1/PD-1 checkpoint inhibition. In our preclinical studies, we have observed enhanced anti-tumor activity compared to checkpoint inhibition alone, and induced
immunological memory in syngeneic mice models with our PD-L1 Boltbody ISAC.
Our Pipeline
We are leveraging our myeloid biology expertise to build a robust pipeline of immune-stimulating, myeloid-engaging therapeutics. Our current
pipeline is represented in the figure below. In addition to the programs below,
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we are also exploring various well-known targets that have been traditionally difficult to drug and where our myeloid expertise and the Boltbody ISAC approach may unlock the potential of these
promising antigens as viable cancer targets. We hold exclusive worldwide rights to all of the listed programs.
In this graphic, HER2 = human epidermal growth factor receptor 2; CEA = carcinoembryonic antigen; PD-L1 = programmed cell death-ligand 1; TAM1 = tumor-associated macrophage 1 antigen; NSCLC = non-small cell lung cancer; CRC = colorectal cancer; and SCLC = small cell
lung cancer.
Our Corporate History and Team
Our company was founded in 2015 to capture the pioneering work of our founder Dr. Edgar G. Engleman, who is Professor of Pathology
and Medicine at Stanford University School of Medicine and Co-Director of the Immunology and Immunotherapy Program of the Stanford Cancer Institute. Dr. Engleman’s expertise in translating cancer
immunotherapeutics from bench to bedside includes the discovery of a dendritic cell-based technology that was the basis for the first active immunotherapy approved by the FDA. It was also at the Engleman Laboratory that the promising new
immunotherapy activating dendritic cells in tumors in situ, without requiring their removal and activation in vitro, was discovered in collaboration with Dr. Yaron Carmi and led to the founding of Bolt Biotherapeutics. Continued
research in the Engleman Laboratory led Dr. Michael Alonso, a scientific co-founder, and Dr. Shelley Ackerman along with Dr. Engleman to invent the technology that formed the basis of our
promising Boltbody ISAC platform.
We have assembled a highly qualified management team with broad experience in myeloid biology, drug
discovery and development to execute our mission. Our scientific founders and our management team collectively have extensive experience in immunology, oncology drug development and patient care. We are industry veterans with prior experience at
companies such as Alder, Astellas, Gilead, Jazz, Roche / Genentech, Sunesis and others. Together, our team has a proven track record in the discovery, development and commercialization of numerous approved therapeutics such as Alecensa, Cytovene,
Evenity, Gazyva, Herceptin, Kadcyla, Polivy, Perjeta, Rituxan, Tecentriq, Valcyte, Venclexta and Vyepti while at other companies. Prior to the completion of our initial public offering in February 2021, we funded our operations primarily through
private placements of our convertible preferred stock for gross proceeds of $173.7 million, including the January 2021 issuance and sale of 5,611,059 shares of Series C-2 preferred stock for net proceeds of $51.9 million. In February 2021, we
completed our initial public offering of 13,225,000 shares of our common stock at a price to the public of $20.00 per share, including the exercise in full by the underwriters of their option to purchase
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1,725,000 additional shares of our common stock. Including this option exercise, the aggregate net proceeds to us from the offering was approximately $241.7 million, net of approximately $22.8
million in underwriting discounts, commissions and other offering expenses.
Strategy
Our goal is to become a leading immuno-oncology company, leveraging our myeloid biology expertise and proprietary Boltbody ISAC approach to
discover, develop and commercialize transformative treatments to address key unmet medical needs in cancer. The key components of our strategy are to:
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Background of Myeloid Cell Biology
Overview of Myeloid Cell Biology in Cancer
Myeloid cells are a group of immune cells that belong to the innate immune system, consisting of cell types known as monocytes, macrophages,
dendritic cells and granulocytes. These cells serve various essential roles in the body’s immune system. In particular, myeloid antigen presenting cells, or myeloid APCs, which include monocytes, macrophages and dendritic cells, are critically
involved in the regulation of T cell responses and thereby bridge our body’s innate and adaptive immune systems. Due to various immunosuppressive factors produced in the tumor microenvironment, the normal function of these cells can be
inhibited and limited in their ability to create a productive anti-tumor immune response. The source of these immunosuppressive factors can be from cancer cells, cancer-associated fibroblasts, tumor-associated neutrophils, T regulatory cells,
tumor-associated macrophages or myeloid-derived suppressor cells. When functioning properly, myeloid APCs can stimulate anti-tumor effects in the body, including direct tumor cell killing by phagocytosis and subsequent activation of T cells to
effect long lasting tumor cell killing. This type of T cell response, which is critical for durable anti-tumor immunity, begins when the Boltbody ISAC targets the antigen-expressing tumor cells for phagocytosis by myeloid APCs such as dendritic
cells. When appropriately activated by a Boltbody ISAC or other stimuli, these myeloid cells transform into effective antigen-presenting cells that can migrate to the lymph nodes to activate tumor antigen-specific T cells that are critical to direct
tumor cell killing. These activated myeloid APCs also secrete pro-inflammatory chemokines and cytokines that help convert immunologically “cold” tumors into “hot” tumors. As such,
tumor-supportive myeloid cells are converted to tumor-destructive myeloid cells, further amplifying the innate and adaptive immune responses and thereby leading to a productive and durable anti-tumor immune response.
Overview of Toll-Like Receptors and Their Use in Cancer
Toll-like receptors, or TLRs, are a class of pattern recognition receptors that bind to molecules present on bacteria, viruses and other
microorganisms. They are highly expressed by myeloid APCs and other innate immune cells and play a key role in the activation of the immune system in response to microbial invasion. Stimulation of the TLRs by their natural ligands or synthetic
agonists induces the secretion of pro-inflammatory cytokines as well as the upregulation of molecules involved in antigen processing and presentation. As part of TLR activation, certain pathogens may be
phagocytosed and digested and their antigens presented to T cells that further enhance the innate immune response. These events culminate in the bridging of the innate and adaptive immune responses leading to the induction of a robust T cell
response by TLR-activated myeloid APCs, which is critical for the development of durable immunity against foreign pathogens and cancerous cells.
TLR7 and TLR8 are often described together in scientific literature due to their high degree of homology and shared function. They are both
intracellular TLRs that detect virus-associated single-stranded RNA (ssRNA) and are expressed at varying levels by myeloid APCs, including monocytes, macrophages and dendritic cells. TLR8 is unique in that its expression is restricted to myeloid
APCs, whereas TLR7 is expressed by myeloid APCs, B cells and plasmacytoid dendritic cells, or pDCs. Furthermore, pDCs produce interferon alpha that amplifies the immune response by bolstering dendritic cell and T cell activity. Importantly, both
TLR7 and TLR8 agonists can strongly activate myeloid APCs and elicit protective T cell responses. Targeting both TLR7 and TLR8 thus activates a broader set of immune cells that contribute to a productive anti-tumor immune response.
TLR agonists have been tested to activate the innate immune response to generate anti-tumor activity. If administered systemically, TLR
agonists by themselves pose a risk of systemic immune activation that can lead
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to cytokine release syndrome. As such, they have been administered via intratumoral injection. Examples of intratumoral TLR approaches include CMP-001,SD-101 and NKTR-262. While TLR agonists may have anti-tumor efficacy as a monotherapy, our publication in Nature indicates that anti-tumor responses can be greatly
augmented if immune stimulants are co-administered with tumor-targeting antibody as the combination enables myeloid cells to more effectively uptake (phagocytosis) and present tumor neoantigens to T
cells. Furthermore, our preclinical data demonstrate that conjugation of TLR agonists to tumor-targeting antibodies greatly enhances anti-tumor activity beyond co-administration of unconjugated TLR
agonists and tumor-targeting antibodies.
Boltbody ISACs Initiate a New Innate Anti-tumor Immune Response which Leads to Adaptive
Immunity with Subsequent Immunological Memory
While the majority of the current immunotherapy approaches are focused largely on the adaptive immune
response, the right-hand side of the above cancer immunity cycle, there remains limited approaches to successfully engage the innate immune response that is depicted on the left-hand (shaded) side of the cancer immunity cycle. Our ISACs are designed
to elicit an all-encompassing immune response by engaging the innate immune system to trigger a new adaptive immune response using a single therapeutic agent.
Current immunotherapies seek to address the immune suppression aspects of tumor survival. While these approaches have had a tremendous impact
on the lives of patients, they also have several shortcomings and limitations:
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We address
each of these pitfalls by engaging an entirely new immune response via our tumor-targeted Boltbody ISACs, which have the potential to safely stimulate the TLRs within the myeloid cells ultimately leading to a T cell-driven anti-tumor response.
Our Boltbody ISAC Approach
Our Boltbody
ISAC approach is pioneering a new category of targeted immunotherapies engineered for systemic administration such that circulating Boltbody ISACs reprogram the tumor microenvironment. In the tumor microenvironment, the Boltbody ISACs initiate
anti-tumor activity through a “Three-Factor Authentication” process that involves the following:
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The “Three-Factor Authentication” process provides an added safety benefit to
ensure that the immune system is selectively targeted and only fully activated when all three steps have been met. This ensures an initially localized immune effect. During the “Three-Factor Authentication,” tumor-associated myeloid APCs
engulf the Boltbody ISAC-bound tumors, become armed with tumor neoantigens, and migrate to the lymph nodes where they mediate the activation and rapid expansion of tumor-reactive T cells to eliminate tumor cells, including those without the initial
target antigen. This process enables the body’s own immune system to determine which neoantigens are most important to eliminate the target tumors. We believe that this represents the development of systemic immunological memory with epitope
spreading to neoantigens that will result in long-term anti-tumor responses in patients.
The Boltbody Immune-Stimulating Antibody Conjugate
We designed our Boltbody ISACs with three primary components: a tumor antigen-targeting antibody, a linker that can be designed either as
cleavable or non-cleavable and a proprietary immune stimulant to activate the patient’s innate and adaptive immune systems. Together these components allow us to believe that our Boltbody ISACs have the
potential to overcome the limitations of existing immunotherapies by triggering both the body’s innate and adaptive immune systems through different stages of the cancer immunity cycle to produce long-term anti-tumor activity.
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The figure below depicts the mechanism of action of our Boltbody ISACs starting with
systemic administration followed by 1) tumor antigen recognition, 2) FcR-dependent phagocytosis and 3) TLR-mediated activation, to target tumors locally and activate the
body’s innate and adaptive immune systems, leading to systemic immunological memory with epitope spreading to neoantigens.
Key Features of Our Boltbody ISAC Approach
We believe the following key features are critical to the successful engineering of Boltbody ISACs and set our approach apart from traditional
immunotherapies. These advantages provide us with the opportunity for robust applications across various solid tumors designed to deliver effective and safe therapeutics to provide durable anti-tumor responses.
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Our Lead Program: BDC-1001
BDC-1001—Overview
Our lead product candidate, BDC-1001, is currently in clinical development for the treatment of
patients with HER2-expressing solid tumors, including those with HER2-low tumors. BDC-1001 provides a compelling example of the potential of Boltbody ISACs to address
unmet medical needs in solid tumors. BDC-1001 is delivered systemically and acts locally by targeting HER2-expressing tumors and related metastatic disease, triggering their destruction by the innate and
adaptive immune systems. BDC-1001 consists of a biosimilar of the humanized monoclonal antibody trastuzumab that is chemically conjugated to one of our proprietary TLR7/8 agonists via a non-cleavable linker. We have observed through our preclinical studies that BDC-1001 is an activator of human myeloid antigen presenting cells that may kill tumors via three
distinct mechanisms: trastuzumab-mediated cell killing, robust immune activation and induction of immunological memory. Our observed preclinical anti-tumor response coupled with a lack of adverse safety signals in our
non-human primate GLP toxicology studies leads us to believe that BDC-1001 offers the potential for long-term and meaningful response for patients with HER2-expressing
cancers, including certain HER2-low tumors. We initiated a Phase 1/2 trial of BDC-1001 in the first quarter of 2020 for the treatment of patients with HER2-expressing
solid tumors. We are currently in the dose escalation portion of the trial and expect to move into Phase 2 dose expansions in 2021. We believe that our preliminary Phase 1/2 data provide us with clinical proof of concept for our HER2 Boltbody ISAC
approach.
BDC-1001—Mechanism of Action
BDC-1001 stimulates anti-tumor activity with a three-pronged approach: direct tumor cell killing by
trastuzumab-mediated mechanisms, localized phagocytosis and elimination of HER2-expressing tumor cells by activated myeloid APCs and durable immunity manifested by T cells reactive to tumor-associated antigens or neoantigens. These mechanisms
are supported by our in vivo data demonstrating tumor elimination and immunological memory when treated with our BDC-1001 surrogates.
The mechanism governing myeloid cell activation is tripartite with BDC-1001 binding to HER2-expressing
tumor cells via the antibody variable region, leading to phagocytosis and tumor cell killing by myeloid APCs expressing Fcg receptors, or FcRs, such as macrophages, dendritic cells and monocytes. Once
internalized, the TLR7/8 agonist attached to BDC-1001 gains access to the phagolysosome and mediates downstream events associated with TLR7/8 activation, including increased cytotoxicity, cytokine secretion,
recruitment of immune effector cells and the processing and presentation of tumor-associated antigens that stimulate T cell-mediated immunity. Taken together, the downstream effects of myeloid APC activation induced by BDC-1001 results in the conversion of immunologically “cold” tumors into “hot” tumors.
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Activated myeloid APCs migrate to the draining lymph nodes following BDC-1001 mediated phagocytosis of HER2-expressing tumor cells. Upon arrival to the draining lymph nodes, activated APCs present the full diversity of potential tumor-associated antigens and neoantigens located
within the phagocytosed tumor cells on peptide-MHC complexes to naïve and antigen experienced or previously exhausted T cells. This process, in conjunction with elevated
co-stimulatory molecule expression following TLR7/8 recognition in myeloid APCs, leads to the polyclonal activation and expansion of T cells. As a result, the patients’ own immune system determines which
are the relevant T cells to mobilize for tumor destruction and subsequent immunosurveillance, providing a compelling example of how an off-the-shelf targeted
immunotherapeutic such as BDC-1001 can deliver a personalized therapeutic outcome.
BDC-1001—Design / Selection Process
To demonstrate the promise of our Boltbody ISAC approach, we sought a target that was well-validated and was present in cancer
indications that continue to have significant unmet medical need. We selected HER2 as the target for our first Boltbody ISAC as it met these criteria and is expressed at high levels in multiple malignancies and remains expressed at a high level in
the majority of patients who unfortunately develop tumor progression while on HER2-targeted therapies. HER2-expressing tumors also tend to be rich in myeloid cells, which BDC-1001 utilizes to initiate the
ISAC-mediated anti-tumor cascade that ultimately resulted in tumor elimination and immunological memory in our various preclinical studies.
We selected a biosimilar of trastuzumab as the antibody backbone for BDC-1001 based on the following
parameters: 1) trastuzumab is a well-validated and successful monoclonal antibody that induces meaningful clinical responses in patients with a well understood safety profile, 2) trastuzumab is effective at promoting antibody-dependent
cellular phagocytosis, or ADCP, which is a key step in unlocking the full power of our mechanism of action, 3) trastuzumab has low rates of immunogenicity in patients, 4) trastuzumab has been commercialized as a biosimilar, thereby making
biosimilars of trastuzumab available for the manufacturing of Boltbody ISACs and 5) our preclinical data demonstrated that trastuzumab-based ISACs outperformed pertuzumab-based ISACs with the same payloads.
The other key design element of a Boltbody ISAC is the linker payload, which is designed to promote immune stimulation. For BDC-1001, the combination of TLR7 and TLR8 was selected as the immune stimulant
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for the following reasons: 1) targeting of an endosomal TLR was desirable when considering the safety of the ISAC, as FcR-mediated uptake into the myeloid
APC is required for access to the TLR, 2) gene expression data demonstrated that TLR7 and TLR8 are largely restricted to expression on cells of myeloid lineage including monocytes, macrophages and dendritic cells, 3) TLR7 is also expressed on B
cells and plasmacytoid dendritic cells, which stimulate type I interferon and antibody responses following stimulation, 4) the expression pattern of murine TLR7 recapitulates the combination of TLR7 and TLR8 expression in the human, which enables us
to use murine tumor models as an appropriate setting to investigate our ISAC-mediated mechanisms and 5) we generated data in preclinical experiments demonstrating that dual TLR7/8 agonists outperformed TLR7-specific and TLR8-specific agonists for
activating myeloid cells. Therefore, we believe that a dual TLR7/8 agonist will enhance the potential for a productive anti-tumor immune response.
BDC-1001 was designed with safety in mind. The final linker-payload selection was motivated by the
goal to demonstrate a favorable safety profile in IND-enabling toxicology studies. Our preclinical data demonstrated that non-cleavable linkers lead to increased myeloid
activation and provide a favorable pharmacokinetic profile and a lack of adverse safety signals, as compared to cleavable linkers. In addition, non-cleavable linkers are also less likely to release an active
TLR agonist, further reducing the potential for systemic toxicity. We selected both a non-cleavable linker and the TLR7/8 agonist payload because it conferred a favorable immunogenicity profile and
pharmacokinetic profile for BDC-1001 in non-human primate studies, and importantly, did not induce cytokine release syndrome. Furthermore, the BDC-1001 linker-payload is cell membrane impermeable which limits off target activity and enables our “Three-Factor Authentication” process for added safety.
BDC-1001—Validation of the HER2 Boltbody ISAC Approach
Boltbody ISACs Outperform Equimolar Mixture of Unconjugated TLR7/8 Agonist and Trastuzumab
To demonstrate that our Boltbody ISAC approach is more potent than the mixture of unconjugated TLR7/8 agonist and trastuzumab, we implanted
mice with a HER2-expressing tumor cell line (HCC1954) and treated mice that have functional murine myeloid cells but are deficient in B, T, and NK cells with our BDC-1001 surrogate, trastuzumab alone or
trastuzumab and an unconjugated TLR7/8 agonist. We observed that a single administration of our BDC-1001 surrogate resulted in markedly improved anti-tumor activity as compared to an equimolar mixture of the
unconjugated TLR7/8 agonist and trastuzumab. Therefore, we believe that covalent attachment of a TLR7/8 agonist to a tumor-targeting antibody such as trastuzumab in the form of a Boltbody ISAC dramatically improves the immunostimulatory outcome and
anti-tumor activity of otherwise intratumorally administered, unconjugated TLR agonists.
Figure 1: BDC-1001
Surrogate Delivers Enhanced Anti-Tumor Activity vs. Unconjugated TLR7/8 Agonist and Trastuzumab
SCID/beige mice were dosed once with 5 mg/kg of
BDC-1001 Surrogate, trastuzumab, or an equimolar mixture of trastuzumab and TLR7/8 agonist. Data are shown as mean and standard error of the mean, or SEM, with 3-5 mice
per group.
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Myeloid APCs Eliminate Tumors via Phagocytosis Following Boltbody ISAC
“Three-Factor Authentication”
To assess that Boltbody ISAC activity is governed by three key factors: tumor-targeting,
FcR engagement and TLR agonism, we performed experiments in which each step was perturbed and measured the subsequent anti-tumor effects. In each experiment, mice were implanted with a HER2-expressing tumor cell line and were randomized when the
tumor volume reached 50 – 75 mm3. The figures below demonstrate that our Boltbody ISACs follow a “Three-Factor Authentication” process, in which tumor-targeting, FcR and TLR
engagement are essential to initiate myeloid mediated tumor destruction, even in the absence of the adaptive immune system.
To
demonstrate the requirement for tumor targeting, mice were treated systemically with our BDC-1001 surrogate, trastuzumab, isotype mAb or isotype ISAC. We observed that while our
BDC-1001 surrogate led to tumor elimination, an isotype ISAC that does not recognize the HER2 tumor antigen showed no anti-tumor activity.
Figure 2: BDC-1001 Surrogate Activity Requires Tumor-Targeting
NSG mice were dosed systemically with 5 mg/kg every 5 days through day 25. Data
are shown as mean and SEM with 5 mice per group.
To demonstrate the requirement for Fc-mediated
engagement and TLR agonism, we altered the ISAC by inactivating the Fc domain (Fc-Null ISAC) or by inactivating the payload (TLR-Null ISAC). In the figure below, mice
were treated systemically with our BDC-1001 surrogate, trastuzumab, Fc-Null ISAC or TLR-Null ISAC. We observed that only the BDC-1001 surrogate mediated anti-tumor activity, confirming the requirement for both Fc-mediated engagement and TLR agonism.
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Figure 3: BDC-1001 Surrogate Activity Dependent on Both FcR
Engagement and TLR Agonism
NSG mice were dosed systemically with 5 mg/kg every 5 days through day 25. Data are
shown as mean and SEM with 5 mice per group.
Lastly, to demonstrate that BDC-1001 activity is
dependent on the presence of phagocytes, tumor cells were implanted into mice, and phagocytes were depleted prior to and during BDC-1001 surrogate treatment using clodronate-loaded liposomes. We observed that
depletion of phagocytes, including myeloid APCs, significantly reduced our BDC-1001 surrogate-mediated anti-tumor activity.
Figure 4: BDC-1001 Surrogate Activity Dependent on Presence of Phagocytes
SCID/Beige were dosed systemically with 5 mg/kg on day 0, 5 and 10. Phagocytes were
depleted using clodronate loaded liposomes through day 21. Data are shown as mean and SEM with 4-6 mice per group.
Boltbody ISAC-stimulated CD8+ Cytotoxic T cells Infiltrate and Eliminate Large
Syngeneic Tumors
To assess the capacity of ISACs to mediate anti-tumor activity in the presence of functional innate and adaptive
immune systems, we utilized an immunologically “cold” syngeneic mouse mammary carcinoma, or MMC, tumor model. To minimize cross-species immunogenicity associated with rat HER2, or rHER2, expression in the MMC tumor, transgenic mice that
endogenously express rat HER2 were used as the host.
In the figure below, mice were implanted with the MMC tumor cell line and the tumors
were allowed to grow until they were very large (~500 mm3) and well established. Mice were then treated systemically with our BDC-1001 surrogate, rHER2 mAb
or isotype ISAC. We observed that systemic administration of the BDC-1001 surrogate was well tolerated and the only agent that led to tumor elimination.
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Figure 5: BDC-1001 Surrogate Mediated Tumor Elimination in Very
Large Well-Established Tumors
FVB Erbb2 transgenic mice were dosed systemically with 5 mg/kg on days 0 and 5. Data are
shown as mean and SEM with 4-7 mice per group.
To demonstrate the induction of immunological
memory, BDC-1001 surrogate treated mice with tumor elimination for >60 days after their last treatment were re-challenged with the MMC tumor cell line; tumor
naïve mice served as implantation controls. We observed that our BDC-1001 surrogate generated immunological memory as the previously treated, tumor-free mice were protected against tumor re-challenge and remained tumor-free without retreatment for the duration of the study.
Figure 6: BDC-1001 Surrogate Generated Immunological Memory
FVB Erbb2 transgenic mice that eliminated their tumors for >60 days after the last
treatment with BDC-1001 surrogate or tumor naïve mice were challenged with MMC tumor cells. Date are shown as mean and SEM with 5 mice per group.
To demonstrate that BDC-1001 also results in a T cell-mediated adaptive immune response, mice were
implanted with the MMC tumor cell line and then pre-treated with anti-CD8 depleting antibody with rIgG2b serving as the
non-depleting control. Mice were then treated with our BDC-1001 surrogate. We observed that BDC-1001 surrogate-driven tumor
regression was heavily dependent on CD8 T cell activity, as depletion of CD8 T cells reduced anti-tumor activity. Furthermore, significant increases in phagocytes and CD8 T cells were measured in tumors following
BDC-1001 surrogate treatment, further supporting a mechanism that bridges the innate and adaptive immune systems.
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Figure 7: BDC-1001 Surrogate Activity Dependent on CD8 T Cell
Activity
FVB Erbb2 transgenic mice were treated systemically with 5 mg/kg at days 0 and 5 with BDC-1001 surrogate or rHER2 mAb. CD8 T cells were depleted through day 21. Data are shown as mean and SEM with 6 mice per group.
Boltbody ISACs Generate Immunological Memory & Evidence of Epitope Spreading Beyond HER2
To demonstrate that BDC-1001 surrogate-induced T cell response and immunological memory extend beyond
HER2-expressing tumor cells, as would be expected if epitope spreading occurred, we developed a CT26 cell line that stably expresses rat HER2 (CT26-rHER2) where approximately 10% of the CT26 cells did not express rHER2 after tumor implantation. We
observed that treatment with BDC-1001 surrogate resulted in tumor elimination in approximately 75% of mice whereas none of the mice treated with the unconjugated antibody had their tumors eliminated. These
data demonstrate that the BDC-1001 surrogate was capable of eliminating tumor cells expressing HER2 as well as those with no HER2 expression, suggesting that BDC-1001
surrogate induced epitope spreading. This is an important observation as human tumors are heterogeneous with regards to cell surface HER2 expression. A tumor determined to be HER2-positive will have tumor cells with varying levels of HER2 expression
and BDC-1001 should be capable of eliminating even those tumor cells with low or no HER2 expression.
We performed a re-challenge experiment to further assess the potential for immunological memory with
epitope spreading. Mice that experienced tumor elimination, i.e. were tumor-free, following BDC-1001 surrogate treatment were re-challenged with the parental CT26 cell
line that lacked rHER2 expression or a genetically distinct tumor cell line, 4T1, in the presence and absence of CD4/CD8 T cells. We observed that mice were protected from re-challenge with the parental CT26
line and that this protection required the presence of CD4/CD8 T cells. Finally, we observed that the development of immunological memory and potential epitope spreading was specific to CT26 as tumor growth of 4T1 tumors was not impacted.
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Figure 8: BDC-1001 Surrogate Elicits Tumor Elimination with
Epitope Spreading and Immunological Memory
Balb/c mice were dosed systemically with 10 mg/kg every 5 days through day 25. Mice that
eliminated their tumors for >21 days after the last treatment with BDC-1001 surrogate or tumor naïve mice were challenged with CT26 tumor cells without rHER2 expression. Data are shown as mean and SEM
with 3-8 mice per group.
BDC-1001 Is an Activator
of Human Myeloid APCs at Various Levels of HER2 Expression
BDC-1001 activates human
myeloid APCs to a greater extent than trastuzumab following co-culture with variable HER2-expressing cancer cell lines. As demonstrated in the figure below, BDC-1001
stimulation led to increased expression of CD86, a co-stimulatory molecule that is essential for T cell activation. BDC-1001 also led to increased expression of the co-stimulatory molecule CD40 and increased TNFα secretion, each of which is indicative of a robust myeloid activation response. Importantly, BDC-1001 activated myeloid
APCs to a similar extent when co-cultured with tumor cell lines expressing high (IHC3+) or lower levels of HER2 (IHC2+ or IHC1+). These data suggest that BDC-1001 can
activate myeloid cells even in the presence of low levels of HER2 surface expression on the tumor cells. These data highlight the potential benefit of BDC-1001 in patients with
HER2-low tumors, currently a population for which trastuzumab is not approved.
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Figure 9: BDC-1001 Activates Human Myeloid APCs in Tumor Co-culture Assays
Pooled myeloid APCs were incubated with the indicated cancer cell line and trastuzumab or
BDC-1001. Median fluorescence intensity of CD86 is shown. Data are shown as mean and SEM from 3 experiments with 18 donors.
In a separate set of experiments, we confirmed the requirement for “Three-Factor Authentication,” as
FcR-mediated internalization was needed to bring the linker-payload inside the cell to drive myeloid activation through TLR7/8 agonism. We also confirmed that BDC-1001
retains native trastuzumab functionality, as determined by HER2 binding and in vitro tumor growth inhibition assays.
BDC-1001 Is Well Tolerated in Non-Human Primates
To
assess the potential safety and tolerability of BDC-1001, we performed a multi-dose non-human primate GLP toxicology study where we administered vehicle, 10, 30 or 90
mg/kg of BDC-1001 at weekly intervals for a total of 4 dose administrations (n=7 per group). We did not observe any BDC-1001-related clinical signs or changes in any of
the in-life observations/examinations (e.g., body weights, respiratory rate, as well as ophthalmological, cardiac and neurological endpoints). Furthermore, we did not observe any
BDC-1001-related changes in the serum cytokines evaluated and there were no BDC-1001-related organ weight changes. As a result, it was concluded that BDC-1001 was well-tolerated in non-human primates and that the no observed adverse effect level, or NOAEL, for BDC-1001 was 90 mg/kg,
the highest dose tested.
BDC-1001—Overview of HER2 Indications and Treatment
Paradigms
HER2 is a proto-oncogene that encodes a transmembrane protein involved in signal transduction pathways that
promote cell growth and differentiation. HER2 protein overexpression and gene amplification have been documented across multiple cancers. Targeting HER2 with mAbs and small molecule tyrosine kinase inhibitors has had a major impact on patients with
HER2-expressing breast and gastric cancer, but there remains a significant unmet medical need on an individual and global patient basis. Our BDC-1001 program seeks to improve therapeutic outcomes for patients
with HER2-expressing tumors across three categories: 1) HER2-positive breast and gastric cancer refractory to existing anti-HER2 therapies, 2) tumors with lower expression of HER2 that are not indicated for approved therapies, and 3) other
HER2-positive tumors not indicated for approved therapies. In addition, the innovative Boltbody ISAC approach of BDC-1001 seeks to address this critically important unmet medical need not only in patients with
the aforementioned advanced tumors, but also to extend that innovation to neoadjuvant and adjuvant settings.
As is widely scientifically
accepted and as shown in a 2015 study in the Cancer Metastasis Review, HER2-positivity (IHC 3+ or gene amplification) has been identified in a wide range of malignancies including breast, gastric, bladder, lung, esophageal, colorectal, ovarian,
salivary gland, pancreatic, cervical cancers and others. Prevalence of HER2 overexpressing or amplified tumors varies across indications.
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Figure 10: Estimated Percentage Prevalence of HER2 Positivity by Protein Expression Across Solid Tumor
Indications
Although there is broad prevalence of HER2 expression across tumor types, HER2-targeting agents have only
been approved for patients with HER2-positive breast and gastric cancers, with HER2-positivity based on protein overexpression or gene amplification. Only trastuzumab is approved for both indications. Additional approved HER2-targeting agents for
HER2-positive breast cancer include the following: pertuzumab, trastuzumab emtansine, trastuzumab-hyaluronidase-oysk, lapatinib, neratinib, and most recently, trastuzumab-deruxtecan and tucatinib.
According to epidemiology data publicly presented by F. Hoffmann-La Roche AG/Genentech, Inc., the 2018
annual drug-treated incidence of breast cancer in the United States and in France, Germany, Italy, Spain and the UK (formerly known as the “EU5”) was estimated to be approximately 477,800 patients in the aggregate. Of these, we estimate
that only approximately 75,800 patients are HER2-positive. We estimate HER2-low patients to be more than 50% of the total population, including approximately 86,900 patients who are IHC2+ without gene
amplification and approximately 155,500 patients who are IHC1+ without gene amplification. We plan to explore this HER2-low population in breast cancer starting with the IHC2+ group first.
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Figure 11: Annual Drug-Treated Breast Cancer Incidence and Established Segments in HER2+ Breast Cancer
Trastuzumab-deruxtecan and tucatinib are important recently approved agents for the treatment of patients
with previously treated advanced HER2-positive breast cancer. While both these agents provide important options for patients with advanced breast cancer, it is important to highlight the large percentage of patients who do not respond to these
therapies or develop tumor progression after initial response. There are no approved treatments for either of these patient groups.
Despite the availability of these HER2-targeted agents, most patients with advanced disease and many with early disease are not cured and
require multiple lines of therapy to achieve disease control, improve quality of life and extend survival. Additionally, there are patients not recognized in the current HER2-positive treatment paradigm such as those with lower HER2-expressing
tumors or with HER2-expressing tumor types other than breast and gastric. This unmet medical need includes patients with other tumor types, such as gastric cancer, NSCLC, CRC and bladder cancer, both for HER2-positive and HER2-low cancers. HER2 protein expression and overexpression have been well documented in a wide range of malignancies. Relative patient numbers for HER2 protein expression in these select tumor types are detailed
in the figure below. This represents a large opportunity for a HER2 therapy utilizing our Boltbody ISAC approach.
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Figure 12: 2020 Estimated Incidence in the U.S. of Selected Tumor Types by HER2 Protein Status
BDC-1001—Clinical Development Overview
We are currently conducting a four-part, Phase 1/2 multiple ascending dose and dose-expansion trial of
BDC-1001 administered as a single agent or in combination with an immune checkpoint inhibitor. We initiated the trial in the first quarter of 2020 and plan to enroll up to 390 patients at 20 or more sites
worldwide. This trial will evaluate safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity in patients with HER2-positive disease (IHC3+ or HER2 gene amplification) as well as patients whose tumors have lower
HER2 expression (defined as IHC2+). Collectively, we call these groups “HER2-expressing.” All patients in our study have metastatic disease and disease progression after prior therapies.
Monotherapy
Combination
with Checkpoint Inhibitor
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Monotherapy—Parts 1 and 3
Combination Therapy with Checkpoint Inhibitor—Parts 2 and 4
Biomarker analyses will be performed and assessed in both tumor tissue and blood. BDC-1001 biological activity will be evaluated by exploring pharmacodynamics or predictive biomarkers that may correlate with activity or help identify patients likely to respond to
BDC-1001 as monotherapy or BDC-1001 in combination with specific anti-cancer therapies. Patients may receive study drug up to 24 months after Cycle 1 and may be followed
for survival up to 2 years after their last dose. They will remain on treatment until confirmed progressive disease, initiation of alternative cancer therapy, unacceptable toxicity, withdrawal of consent or if other reasons to discontinue treatment
occur.
BDC-1001—Preliminary Clinical Results
As of January 29, 2021, we have enrolled 20 patients across four cohorts at escalating dose levels. The lowest dose cohort of 0.15 mg/kg
required a single patient to assess tolerability to proceed to the next dose level. Each subsequent cohort enrolls an initial three patients to evaluate for dose-limiting toxicities, after which we are able to enroll up to an additional 12 patients
to such cohort and escalate to the next dose level if the safety criteria are met. We enrolled one patient in the 0.15 mg/kg cohort and three patients in the 0.5 mg/kg cohort. These dose levels were well tolerated by all four patients and they
completed the safety evaluation period without incident. Neither dose was expected to be therapeutically active based on our preclinical modeling. We enrolled four patients, which includes one additional patient, in the 2 mg/kg cohort and we have
enrolled 12 patients, which includes nine additional patients, in the 5 mg/kg cohort. In the 2 mg/kg and 5 mg/kg cohorts, we have observed early signs of clinical activity as well as changes in pharmacodynamic biomarkers that we believe are
consistent with our proposed mechanism of action.
In the 2 mg/kg cohort, we enrolled four patients with the following cancers: biliary,
gastric, rectal and uterine. These patients remained on study with treatment duration ranging from five weeks to 17 weeks, to date. We observed one unconfirmed stable disease in the patient with rectal cancer, who remained on study for
11 weeks. We also observed confirmed stable disease in the patient with microsatellite-stable uterine cancer with visceral lung metastases. This patient remains on study, has received six doses of
BDC-1001 and is in her 17th week of treatment.
In the 5 mg/kg cohort, we have enrolled 12
patients as of January 29, 2021, with the following cancers: cervix, uterine, colon, esophageal, GE junction, rectal, lung, salivary ductal and bladder. Five patients remain on study at this dose level with treatment durations ranging up to 12
weeks, to date. We observed stable disease in two patients with microsatellite-stable colorectal cancer, both of whom have visceral lung or both lung and liver
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metastases. Both of these patients remain on study and had their first CT scan at six weeks, after two doses of BDC-1001. We have also observed a confirmed
partial response in a patient with microsatellite-stable colorectal cancer. The first CT scan for this patient demonstrated a 36% reduction in the sum of the longest diameters of all four measurable tumor lesions. Their second CT scan at 12 weeks
demonstrated a 39% reduction in the sum of the longest diameters of all four measurable tumor lesions, and qualified as a confirmed partial response using RECIST 1.1 criteria. This patient remains on study, and is in his 12th week of treatment.
BDC-1001 has been well tolerated to date in all 20 patients. All subjects have completed their 21-day DLT evaluation period (excluding the 20th patient who was recently enrolled and is still in the DLT period) and no DLTs or drug-related serious adverse events have been observed. Treatment-emergent adverse
events deemed to be related to BDC-1001 have been mild or moderate in severity, including mild infusion-related reactions without interruption to dosing. We continue to enroll patients in the study and we are
proceeding to open enrollment in the next higher dose level cohort at 8 mg/kg.
In addition to our clinical observations, elevations in
pharmacodynamic markers such as plasma cytokines and chemokines were observed with a trend towards greater magnitude in patients with increasing dose level. These include increases in plasma levels of MCP-1,
MIP1α and IP-10, which are chemokines consistent with myeloid cell activation. We have also observed transient increases in plasma levels of TNFα, an indicator of TLR activation. The plasma cytokine
and chemokine data are consistent with our preclinical data and we believe they are also consistent with the proposed mechanism of action of BDC-1001.
We are currently in the Part 1 dose escalation portion of the trial and expect to move into monotherapy Phase 2 dose expansions, as well as
the dose escalation evaluating the combination with an immune checkpoint inhibitor, in 2021.
BDC-2034
Our second program focuses on CEA, a well-known tumor antigen that is overexpressed in various solid tumors with significant unmet medical need
including, but not limited to, colorectal cancer, non-small cell lung cancer, pancreatic cancer and breast cancer. CEA is upregulated on the cell surface of these cancers and displays minimal receptor-mediated
internalization into the cancer cell. In our preclinical studies, we have observed promising anti-tumor activity in vivo with potent in vitro ADCP.
Immune profiling of various solid tumors has revealed that myeloid cells are present in immunologically “hot” and “cold”
tumors. Immunologically “cold” tumors include, but are not limited to, colorectal cancer and pancreatic cancer. CEA is overexpressed in these immunologically “cold” cancers. We believe that this, combined with the aforementioned
properties, makes CEA-expressing tumors an attractive therapeutic opportunity for our Boltbody ISAC approach. We anticipate advancing our CEA Boltbody ISAC, designated
BDC-2034, into the clinic in 2022.
Preclinical Data
In our preclinical experiments we have identified a CEA-targeting mAb that has the desired CEA binding
properties as well as selectivity over other key members of the CEACAM family. We believe this selectivity will reduce unwanted off-target effects that could lead to safety complications. The favorable binding
properties of this mAb will permit increased residence time on CEA to permit an opportunity for myeloid cells to engage the Fc portion of the CEA mAb through Fc receptors.
We also tested the ability of CEA-targeting mAbs to invoke activity in a cellular-based assay that
measures ADCP. We observed that our lead CEA-targeting mAb (CEA mAb) has prominent ADCP activity relative to other mAbs tested. We believe this serves as a strong foundational mAb for BDC-2034 since ADCP is a key part of the ISAC mechanism that leads to a productive anti-tumor immune response.
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To assess the potential efficacy of our CEA Boltbody ISAC program targeting CEA-expressing tumors, we conducted in vivo xenograft experiments in mice engrafted with the human pancreatic cancer cell line HPAFII. The cell surface expression of CEA on HPAFII tumors is believed to
represent the typical CEA expression levels found in human pancreatic cancers. In this study we compared the anti-tumor activity of our lead CEA mAb to a CEA Boltbody ISAC (CEA ISAC). In addition, we also compared both of these groups to mice that
did not receive either therapy (Untreated). Measuring tumor volumes throughout the course of the study revealed that the HPAFII model was refractory to naked CEA mAb with no evidence of anti-tumor activity compared to the Untreated group of animals.
In contrast, CEA ISAC displayed anti-tumor activity in all animals. We believe that these data support continued research and development of BDC-2034 for patients with
CEA-expressing cancers.
Figure 13: In vivo Activity of CEA Boltbody ISAC in HPAFII Human
Pancreatic Xenograft Model
SCID/beige mice were dosed systemically with 5 mg/kg every 5 days through day 15.
Data are shown as mean and SEM with 6 mice per group.
PD-L1 Program
Our third program, a PD-L1 Boltbody ISAC, focuses on another area with significant unmet medical need,
the treatment of patients with tumors that are nonresponsive or become refractory to immune checkpoint blockade, such as NSCLC, CRC, breast and other cancers. PD-L1 is an immune checkpoint protein that can be
expressed on cancer and immune cells. Expression of PD-L1 on the cell surface of these cells engages the PD-1 checkpoint and results in the inhibition of a productive
anti-tumor immune response. More specifically, T cell-mediated immune responses are significantly dampened since the expression of PD-L1 on the cancer cells engages with the
PD-1 on the cell surface of T cells and acts as a brake on the immune system. Inhibition of the PD-L1/PD-1 axis has shown potent
anti-tumor immune responses in numerous types of cancers; however, a substantial number of cancer patients’ tumors are non-responsive or become refractory to immune checkpoint blockade. These patients
with checkpoint refractory tumors represent a significant unmet medical need. We believe that a PD-L1 Boltbody ISAC has the potential to overcome the limitations of current anti-PD-L1 therapies.
Our PD-L1 Boltbody ISAC is
designed to be a trifunctional therapeutic to overcome such limitations. As such, our PD-L1 ISAC is built to elicit: 1) antibody-dependent cellular phagocytosis of the tumor, 2) activation of myeloid
cells in the tumor microenvironment to enhance neoantigen presentation and consequential T cell-dependent tumor killing and immunological memory, and 3) inhibition of the PD-L1/PD1 axis that can
thwart T cell-dependent responses.
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Preclinical Data
In our preclinical experiments, we have identified
PD-L1-targeting mAbs that have the desired activity in a cellular-based assay that measures ADCP. Our
PD-L1-targeting mAbs have ADCP activity and meet the criteria for the PD-L1 Boltbody ISAC given ADCP is a key part of the ISAC
mechanism that leads to a productive anti-tumor immune response.
PD-1/PD-L1 blockade is a key property for our desired PD-L1 Boltbody ISAC in order to endow the molecule with a trifunctional mechanism of action. In our preclinical experiments, we observed the ability of our PD-L1-targeting mAbs to disrupt the PD-L1/PD-1 interaction in a cellular-based reporter assay. All three of our top PD-L1-targeting mAbs show robust PD-L1/PD-1 blockade. We believe this property within a PD-L1 Boltbody ISAC would provide a substantial increase in the capacity to elicit a robust anti-tumor immune response.
To further assess and characterize the PD-1/PD-L1 blockade
capacity of each of our PD-L1 mAbs, we conducted mixed lymphocyte reaction, or MLR, in vitro assays experiments. All three of our top
PD-L1-targeting mAbs demonstrated robust production of IFNg, a cytokine produced as a result of PD-L1/PD-1 blockade. These data, combined with the PD-L1/PD-1 blockade cellular reporter assay,
suggest that our PD-L1 mAbs have the desired PD-L1/PD-1 blockade function required for a
PD-L1 Boltbody ISAC.
To assess the potential efficacy of our
PD-L1 Boltbody ISAC program targeting PD-L1-expressing tumors, we conducted in vivo syngeneic experiments in mice
engrafted with the murine colorectal cancer cell line, MC38 that expresses human PD-L1. In this preclinical study we compared the tumor elimination of one of our PD-L1-targeting mAb (PD-L1 mAb) to the same PD-L1-targeting mAb conjugated to a murine
TLR7 agonist (PD-L1 ISAC). In addition, we also compared both of these groups to animals that received a non-tumor-targeting mAb (isotype mAb). We observed that MC38-hPD-L1 was partially sensitive to our PD-L1-targeting mAbs relative to the isotype mAb-treated animals; however, no complete responses were observed. In contrast, PD-L1 ISAC displayed marked tumor elimination with complete responses observed in 75% of
animals tested. We believe that these data support continued research and development of a PD-L1 Boltbody ISAC for
PD-L1-expressing cancers for the potential treatment of patients with checkpoint refractory tumors.
Figure 14: In vivo Activity of PD-L1 Boltbody ISAC in MC38-hPD-L1 Colorectal Syngeneic Tumor Model
C57BL/6J mice were dosed systemically with 5 mg/kg every 3 days through day 9. Data are
shown as mean and SEM with 4 mice per group.
Myeloid Modulators and Future Research
Our expertise in myeloid biology and immuno-oncology has led us to research various tumor antigens across solid tumors where significant unmet
medical need remains. In addition, we have expertise in modulating
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the various properties of a Boltbody ISAC that would further optimize the profile for any particular tumor antigen in our research and discovery programs. Our Boltbody ISAC approach is designed
to elicit a robust anti-tumor immune response with a favorable safety profile. We believe this approach has the potential to enable us to develop product candidates to treat patients with a wide variety of tumors.
Our expertise may lead to additional research and discovery programs that are independent, but may complement, our Boltbody ISAC approach and
our growing library of innate immune stimulators. Importantly, tumor-associated myeloid cells tend to be tumor-supportive rather than tumor destructive. Additional ways of modulating tumor-associated myeloid cells are warranted given the
heterogeneity of human cancers with respect to tumor mutational burden as well as immunological profile. Our research and discovery efforts are exploring additional immune agonists for the Boltbody ISAC approach as well as identifying novel targets
in tumor-associated myeloid cells that can be targeted with other therapeutic modalities.
An example from these efforts is shown in the
figure below where we have identified mAbs (Antibodies 1-4) in our laboratories that are capable of binding to and agonizing a novel cell surface protein, which we refer to as TAM1, on tumor-supportive
macrophages. TAM1 agonism results in the production of pro-inflammatory cytokines more consistent with the characteristics of tumor-destructive myeloid cells. We believe such molecule may have the potential to
reprogram tumor-supportive macrophages into tumor-destructive macrophages to elicit a productive anti-tumor immune response. Additionally, KRAS and TP53 mutations may upregulate TAM1 on tumor-associated myeloid cells and could provide an avenue to
develop precision medicine with an immune modulator.
Figure 15: Capacity of TAM1 Binding mAbs to Enhance TNFα Secretion from
Tumor-Supportive Macrophages
TNFα secretion by human M-CSF differentiated
macrophages stimulated with TAM1 binding mAbs for 20 hours. Data are shown as mean and SEM with 5 donors.
License and Collaboration Agreements
License Agreements with Stanford University
In May 2015, we entered into a license agreement with Stanford, or the 2015 Stanford Agreement, pursuant to which Stanford granted us a
worldwide exclusive, sublicenseable license under certain patents related to our proprietary Boltbody ISAC technology, to develop, manufacture and commercialize licensed products incorporating such technology. In consideration for the rights granted
to us under the 2015 Stanford Agreement, we paid Stanford a nominal nonrefundable license issue fee and issued Stanford and two co-inventors an aggregate of 52,401 shares of our common stock. Stanford retained
the right under the 2015 Stanford Agreement, on behalf of itself and all other non-profit research institutions, to practice the licensed patents for any non-profit
purpose, including sponsored research and collaborations, but excluding delivery of paid or reimbursed healthcare. However, Stanford retained the right to practice the licensed patents for the delivery of its own paid or reimbursed healthcare.
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In June 2018, we entered into a second license agreement with Stanford, or the 2018 Stanford
Agreement, and collectively with the 2015 Stanford Agreement, the Stanford Agreements. Pursuant to the 2018 Stanford Agreement, Stanford granted us a worldwide exclusive license, under certain patents related to myeloid modulation for cancer
immunotherapy to develop, manufacture and commercialize products containing such technology. In consideration for the rights granted to us under the 2018 Stanford Agreement, we paid Stanford a nominal nonrefundable license issue fee and reimbursed
Stanford for past patent expenses, together totaling less than $0.1 million. Stanford retained the right under the 2018 Stanford Agreement, on behalf of itself, Stanford Health Care, Lucile Packard Children’s Hospital at Stanford and all
other non-profit research institutions, to practice the licensed patents for any non-profit purpose, including sponsored research and collaborations. The licensed
patents are additionally subject to a nonexclusive, worldwide license held by the Howard Hughes Medical Institute to exercise such intellectual property rights for research purposes, with the right to sublicense to
non-profit and governmental entities.
The technology claimed by the patents licensed under both
Stanford Agreements was developed using U.S. government funding and the licenses are therefore subject to a nonexclusive license held by the U.S. government, certain requirements that licensed products be manufactured in the United States (unless
waived according to U.S. government process) and U.S. government march-in rights. For more information on risks related to technology developed using government funding see “Risk Factors—Risks
Related to Our Intellectual Property.”
Under each Stanford Agreement, we are obligated to pay annual license maintenance fees, which
are nominal and will be creditable against any royalties payable to Stanford under such agreement in the applicable year. We are required in each Stanford Agreement to make milestone payments up to an aggregate of $0.4 million for the first
licensed product under such agreement that meets certain patent issuance, clinical and regulatory milestones, and an additional milestone payment of $0.2 million for each additional regulatory approval. We also agreed in each Stanford Agreement
to pay Stanford tiered royalties on our and our sublicensees’ net sales of licensed products, at low single-digit percentage rates, subject to certain customary reductions. Our royalty obligations continue for the term of each Stanford
Agreement and we are required to pay royalties on any licensed products made, used, imported or offered for sale during the term of such agreement but sold after the term of the agreement. In addition, we are obligated in each Stanford Agreement to
pay Stanford a sub-teen double digit to low teen double-digit percentage of certain consideration we receive as a result of granting sublicenses to the licensed patents. Pursuant to each Stanford Agreement, we
will reimburse Stanford’s patent expenses, including reasonable costs incurred in assisting us with prosecuting and maintaining licensed patents.
Under each Stanford Agreement, we are obligated to use commercially reasonable efforts to develop and commercialize licensed products and we
are also required to achieve certain funding, development and/or regulatory milestones by certain dates, which can be extended a limited number of times upon the payment of a nominal fee.
The Stanford Agreements continue until terminated. We may terminate either of the Stanford Agreements at any time for any reason by providing
at least 30 days’ written notice to Stanford. Stanford may terminate either of the Stanford Agreements if we breach certain provisions of such Stanford Agreement, including the payment and funding, development and/or regulatory milestone
obligations, and fail to remedy such breach within 60 days after written notice of such breach by Stanford.
Joint Development and
License Agreement with Toray Industries
In March 2019, we entered into the Toray Development Agreement to develop and
commercialize collaboration products, each containing a proprietary antibody owned by Toray, or the Toray Antibody, or a related antibody against the same novel tumor antigen target, and our Boltbody technology, for cancer in the United States,
Japan and the European Union, or the Territory. In conjunction with the Toray Development Agreement, Toray purchased 717,514 shares of our preferred stock at an aggregate purchase price of $10.0 million.
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Under the Toray Development Agreement, we granted Toray a
co-exclusive (with us) license under certain of our patents and know-how related to our Boltbody technology, and we received from Toray a
co-exclusive (with Toray) license under certain of its patents and know-how related to the Toray Antibody. Both co-exclusive
licenses are limited to the development, manufacture and commercialization of collaboration products in the Territory for the diagnosis, treatment and prevention of a specified number of cancer indications to be selected by the parties, or the