GTBP US Equity☆

Item 1A. Risk Factors 9

Item 1B. Unresolved Staff Comments 32

Item 2. Properties 32

Item 3. Legal Proceedings 32

Item 4. Mine Safety Disclosures 32

Item 6. [Reserved] 33

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 40

Item 8. Financial Statements and Supplementary Data 40

Item 9A. Controls and Procedures 40

Item 9B. Other Information 41

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 41

PART III 41

Item 10. Directors, Executive Officers and Corporate Governance 41

Item 11. Executive Compensation 42

Item 14. Principal Accounting Fees and Services 42

Item 15. Exhibits and Financial Statement Schedules 43

PART

I

CAUTIONARY

NOTICE REGARDING FORWARD-LOOKING STATEMENTS

This

Annual Report on Form 10-K, including any documents which may be incorporated by reference into this Annual Report,

contains “Forward-Looking Statements” within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section

21E of the Securities Exchange Act of 1934, as amended. All statements other than statements of historical fact are “Forward-Looking

Statements” for purposes of these provisions, including our plans of operation, any projections of revenues or other financial

items, any statements of the plans and objectives of management for future operations, any statements concerning proposed new products

or services, any statements regarding future economic conditions or performance, and any statements of assumptions underlying any of

the foregoing. All Forward-Looking Statements included in this document are made as of the date hereof and are based on information available

to us as of such date. We assume no obligation to update any Forward-Looking Statement. In some cases, Forward-Looking Statements can

be identified by the use of terminology such as “may,” “will,” “expects,” “plans,” “anticipates,”

“intends,” “believes,” “estimates,” “potential,” or “continue,” or the negative

thereof or other comparable terminology. Although we believe that the expectations reflected in the Forward-Looking Statements contained

herein are reasonable, there can be no assurance that such expectations or any of the Forward-Looking Statements will prove to be correct,

and actual results could differ materially from those projected or assumed in the Forward-Looking Statements. Future financial condition

and results of operations, as well as any Forward-Looking Statements are subject to inherent risks and uncertainties, including any other

factors referred to in our press releases and reports filed with the Securities and Exchange Commission. All subsequent Forward-Looking

Statements attributable to the company or persons acting on its behalf are expressly qualified in their entirety by these cautionary

statements. Additional factors that may have a direct bearing on our operating results are described under “Risk Factors”

and elsewhere in this Annual Report on Form 10-K.

Introductory

Comment

Throughout

this Annual Report on Form 10-K, the terms “GT Biopharma,” “GTBP,” “we,” “us,”

“our,” “the company” and “our company” refer to GT Biopharma, Inc., a Delaware corporation formerly

known as DDI Pharmaceuticals, Inc., Diagnostic Data, Inc. and Oxis International, Inc., together with our subsidiaries.

ITEM

1. BUSINESS

We

are a clinical stage biopharmaceutical company focused on the development and commercialization of novel immuno-oncology products based

on our proprietary Tri-specific Killer Engager (TriKE®) fusion protein immune cell engager technology platform. Our TriKE®

platform generates proprietary therapeutics designed to harness and enhance the cancer killing abilities of a patient’s

own natural killer cells, or NK cells. Once bound to an NK cell, our moieties are designed to enhance the NK cell, and precisely direct

it to one or more specifically targeted proteins expressed on a specific type of cancer cell or virus infected cell, resulting in the

targeted cell’s death. TriKE®s can be designed to target any number of tumor antigens on hematologic malignancies

or solid tumors and do not require patient-specific customization.

We

are using our TriKE® platform with the intent to bring to market immuno-oncology products that can treat a range

of hematologic malignancies, and solid tumors. The platform is scalable, and we are putting processes in place to be able to produce

investigational new drug (IND) ready moieties in a timely manner after a specific TriKE® conceptual design.

Specific drug candidates can then be advanced into the clinic on our own or through potential collaborations with partnering companies.

We believe our TriKE®s may have the ability, if approved for marketing, to be used as both monotherapy and in combination

with other standard-of-care therapies.

We

are also using our TriKE® platform to develop therapeutics useful for the treatment of infectious disease such

as for the treatment of patients infected by the human immunodeficiency virus (HIV). While the use of anti-retroviral drugs has substantially

improved the health and increased the longevity of individuals infected with HIV, these drugs are designed to suppress virus replication

to help modulate progression to acquired immunodeficiency syndrome (AIDS) and to limit further transmission of the virus. Despite

the use of anti-retroviral drugs, infected individuals retain reservoirs of latent HIV-infected cells that, upon cessation of anti-retroviral

drug therapy, can reactivate and re-establish an active HIV infection. For a curative therapy, destruction of these latent HIV infected

cells must take place. The HIV-TriKE® contains the antigen binding fragment (Fab) from a broadly neutralizing antibody

targeting the HIV-Env protein. The HIV-TriKE® is designed to target HIV while redirecting NK cell killing specifically

to actively replicating HIV infected cells. The HIV-TriKE® induced NK cell proliferation and demonstrated the ability

in vitro to reactivate and kill HIV-infected T-cells. These findings indicate a potential role for the HIV-TriKE®

in the reactivation and elimination of the latently infected HIV reservoir cells by harnessing the NK cell’s ability to mediate

the antibody-directed cellular cytotoxicity (ADCC).

Our

initial work has been conducted in collaboration with the Masonic Cancer Center at the University of Minnesota under a program led by

Dr. Jeffrey Miller, the Deputy Director. Dr. Miller is a recognized leader in the field of NK cell and IL-15 biology and their therapeutic

potential. We have exclusive rights to the TriKE® platform and are generating additional intellectual property

for specific moieties.

Immuno-Oncology

Platform

Tri-specific

Killer Engagers (TriKE®s)

The

generation of chimeric antigen receptor, or CAR, expressing T cells from monoclonal antibodies has represented an important step forward

in cancer therapy. These therapies involve the genetic engineering of T cells to express either CARs, or T cell receptors, or TCRs, and

are designed such that the modified T cells can recognize and destroy cancer cells. While a great deal of interest has recently been

placed upon chimeric antigen receptor T, or CAR-T, therapy, it has certain limitations for broad potential applicability because it can

require an individual approach that is expensive, time consuming, and may be difficult to apply on a large scale. NK cells represent

an important immunotherapeutic target as they are involved in tumor immune-surveillance, can mediate antibody-dependent cell-mediated

cytotoxicity (ADCC), contain pre-made granules with perforin and granzyme B and can quickly secrete inflammatory cytokines, and unlike

T cells they do not require antigen priming and can kill cells in the absence of major histocompatibility complex (MHC) presentation

of antigens. Unlike full-length antibodies, TriKE® constructs are composed of a single-chain fusion protein that

binds the CD16 receptor of NK cells directly producing a potent and lasting cytotoxic killing response, interleukin 15 (IL-15) to promote

NK cell activation, persistence and proliferation, and a cancer cell targeting moiety. An additional benefit of TriKE®

may have been its attractive biodistribution, as a consequence of their smaller size, which we expect to be important in the

treatment of solid tumors. In addition to these advantages, TriKE® is designed to be non-immunogenic, have appropriate

clearance properties, and can be engineered to target a variety of tumor antigens.

We

believe there is a continued unmet medical need for targeted immuno-oncology therapies that can have the potential to be dosed in a patient-friendly

outpatient setting, can be used on a stand-alone basis, augment the current monoclonal antibody therapeutics, or be used in conjunction

with more traditional cancer therapy. We believe our TriKE® constructs have this potential and therefore we have

generated, and intend to continue to generate, a pipeline of product candidates to be advanced into the clinic on our own or through

potential collaborations with larger companies.

GTB-3550 TriKE® and Phase 1 Acute Myeloid

Leukemia/Myelodysplastic Syndrome (AML/MDS) Phase 1 Clinical Trial

GTB-3550

is the Company’s first-generation TriKE® product candidate which is a single-chain, tri-specific recombinant

fusion protein construct composed of the variable regions of the heavy and light chains of anti-CD16 and anti-CD33 antibodies and a modified

form of IL-15. The GTB-3550 Phase 1 clinical trial for treatment of patients with CD33-expressing, high risk myelodysplastic syndromes

and refractory/relapsed acute myeloid leukemia opened for patient enrollment September 2019 and completed enrollment in September 2021.

The clinical trial was conducted at the University of Minnesota’s Masonic Cancer Center in Minneapolis, Minnesota under the direction

of Dr. Erica Warlick and Dr. Mark Juckett.

Background

and Select Non-Clinical Data

In

conjunction with our research agreement with the Masonic Cancer Center at the University of Minnesota, the exploration of targeting NK

cells to a variety of tumors initially focused on novel bi-specific killer engagers, or BiKEs, composed of the variable portions of antibodies

targeting the CD16 activating receptor on NK cells and CD33 (AML and MDS; see figure below), B7H3 (solid tumors – breast, lung,

colon, prostate), PD-L1 (solid tumors), Her2 (Breast, Gastric), or CD19/CD22 (B cell lymphomas) on the tumor cells.

Subsequently,

a tri-specific (TriKE®) construct that replaced the linker molecule between the CD16 scFv and the CD33 scFv with

a modified IL-15 molecule, containing flanking sequences, was generated, and tested. Data indicates that the CD16 x IL-15 x CD33

potently induce proliferation of healthy donor NK cells, possibly greater than that induced by exogenous IL-15, which is absent in the

BiKE platform. Targeted delivery of the IL-15 through the TriKE® also resulted in specific expansion of the NK

cells without inducing T cell expansion on post-transplant patient samples.

When

compared to the CD16 x CD33 BiKE, the CD16 x IL-15 x CD33 TriKE® is also capable of potently restoring killing

capacity of post-transplant NK cells against CD33-expressing HL-60 targets and primary AML blasts. These results demonstrated the ability

to functionally incorporate an IL-15 cytokine into the BiKE platform and also demonstrated the possibility of targeting a variety

of cytokines directly to NK cells while reducing off-target effects and the amount of cytokines needed to obtain biologically relevant

function.

The

figure below is a schematic of a BiKE construct (top) and a TriKE® construct (bottom), which has the modified IL-15

linker between the CD16 scFv and the CD33 scFv components.

The

TriKE® constructs were also tested against three separate human tumor cell lines: HL-60 (promyelocitic leukemia),

Raji (Burkitt’s lymphoma), and HT29 (colorectal adenocarcinoma), in addition to a model for ovarian cancer. All cell lines contained

the Luc reporter to allow for in vivo imaging of the tumors. These systems were used to show in vivo efficacy of BiKE (1633) and TriKE®

(GTB-3550) against relevant human tumor targets (HL-60-luc) over an extended period of time. The system consisted of initial

conditioning of mice using radiation (250-275 cGy), followed by injection of the tumor cells (I.V. for HL-60-luc and Raji-luc, intra-splenic

for HT29-luc and IP for ovarian for MA-148-luc), a three-day growth phase, injection of human NK cells, and repeated injection of the

drugs of interest, BiKE and TriKE® (three to five times a week). Imaging was carried out at Day 7, 14, and 21,

and extended as needed.

The

figure below shows the results (tumor burden and mortality) when dosing NK cells alone (top panel), the BiKE version (lacking IL-15)

of GTB-3550 (middle panel; called 1633), and the TriKE®, GTB-3550 (bottom panel; then called 161533) in the above

human tumor model, HL-60-luc. In the NK-cell-only arm, two out of the five mice were dead by Day 21 with two of the surviving mice having

extensive tumor burden as depicted by the colored images. In contrast, all five mice in each of the BiKE and TriKE®

arms survived. In addition, the tumor burden in the TriKE®-treated mice was significantly less than in the BiKE-treated

mice, demonstrating the improved efficacy from NK cells in the TriKE®-treated mice.

Based

on these results, and others, the IND for GTB-3550 was filed in June 2017 by the University of Minnesota. The FDA requested that

additional preclinical toxicology, additional information and clarifications on manufacturing, and clinical development plans. The requested

additional information and clarifications were completed and incorporated into the IND in eCTD format. We filed the IND amendment in

June 2018 and announced on November 1, 2018, that the FDA granted approval of the IND and the Company was authorized to initiate a first-in-human

Phase 1 study with GTB-3550 in AML, MDS, and severe mastocytosis. The Phase 1 clinical trial was initiated in September 2019 and closed

in September 2021.

Targeting

Solid Tumors and Other Potentially Attractive Characteristics

Unlike

full-length antibodies, TriKE® is composed of a single-chain fusion protein that binds the CD16 receptor of NK

cells directly producing a potentially more potent and lasting response as demonstrated by preclinical studies. An additional benefit

due to the smaller size of TriKE® is enhanced biodistribution which we expect to be important in the treatment

of solid tumors. In addition to these potential advantages, TriKE® is designed to be non-immunogenic, have appropriate

clearance properties and can be engineered quickly to target a variety of tumor antigens. We believe these attributes make them an ideal

pharmaceutical platform for potentiated NK cell-based immunotherapies and have the potential to overcome some of the limitations of CAR-T

therapy and other antibody therapies.

Examples

of our earlier stage solid tumor targeting product candidates are focused on CD33, B7-H3, Her2, PD-L1, CD19, CLEC12A, CD22, and CD133

alone and in combination. We believe these constructs have the potential to target prostate, breast, colon, ovarian, liver,

and head and neck cancers. Depending on the availability of drug supply, we hope to initiate human clinical testing for certain of our

solid tumor product candidates in 2023.

Efficient

Advancement of Potential Future Product Candidates – Production and Scale Up

We

are using our TriKE® platform with the intent to bring to market multiple immuno-oncology products that can treat

a range of hematologic malignancies and solid tumors. The platforms are scalable, and we are currently working with a third-party

product manufacturer investigating the optimal GMP production expression system for TriKE® constructs.

We

believe TriKE®s will have the ability, if approved for marketing, to be used as both monotherapy and in combination

with standard-of-care therapies.

Immuno-Oncology

Product Candidates

GTB-3550

GTB-3550

was our first TriKE® product candidate. It reflected our first-generation TriKE® platform.

It is a single-chain, tri-specific scFv recombinant fusion protein conjugate composed of the variable regions of the heavy and light

chains of anti-CD16 and anti-CD33 antibodies and a modified form of IL-15. We studied this anti-CD16-IL-15-anti-CD33 TriKE®

in CD33 positive leukemias, a marker expressed on tumor cells in acute myelogenous leukemia, or AML, myelodysplastic syndrome,

or MDS. CD33 is primarily a myeloid differentiation antigen with endocytic properties broadly expressed on AML blasts and, possibly,

some leukemic stem cells. CD33 or Siglec-3 (sialic acid binding Ig-like lectin 3, SIGLEC3, SIGLEC3, gp67, p67) is a transmembrane receptor

expressed on cells of myeloid lineage. It is usually considered myeloid-specific, but it can also be found on some lymphoid cells. The

anti-CD33 antibody fragment used for these studies was derived from the M195 humanized anti-CD33 scFV and has been used in multiple human

clinical studies. It has been exploited as target for therapeutic antibodies for many years. We believe the recent approval of the antibody-drug

conjugate gemtuzumab validates this targeted approach.

GTB-3550

is being replaced by a more potent next-generation camelid nanobody TriKE®, GTB-3650, targeting CD33 positive

relapsed/refractory Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS).

About

High-Risk Myelodysplastic Syndromes

Myelodysplastic

Syndromes is a rare form of bone marrow-related cancer caused by irregular blood cell production within the bone marrow. As a result

of this irregular production, MDS patients do not have sufficient normal red blood cells, white blood cells and/or platelets in circulation.

High-risk MDS is associated with poor prognosis, diminished quality of life, and a higher chance of transformation to acute myeloid leukemia.

The goals of therapy are to reduce disease associated symptoms and the risk of disease progression and death, thereby improving both

quality and quantity of life. United States incidence of MDS is estimated to be 10,000 cases per year, although the condition is thought

to be under diagnosed. The prevalence has been estimated to be from 60,000 to 170,000 in the United States. Approximately 40% of patients

with High-Risk MDS transform to AML, another aggressive cancer with poor outcomes.

About

Acute Myeloid Leukemia

Acute

myeloid leukemia is a type of cancer in which the bone marrow makes abnormal myeloblasts (a type of white blood cell), red blood

cells, or platelets. The median age at the time of diagnosis is 65–69 years. AML is an aggressive disease and is fatal without

anti-leukemic treatment. Among patients treated with chemotherapy, 65% to 80% achieve complete remission. Despite a plethora of novel

agents that have been approved by the U.S. Food and Drug Administration since 2017 for treatment of AML, once complete remission (CR)

is achieved, approximately 50% of patients age < 60 years of age and up to 90% of patients ≥ 60 years of age will relapse, despite

consolidation strategies. Furthermore, while 10–40% of younger AML patients are primarily refractory to AML induction therapy,

the number is considerably higher for patients above 60 years (40–60%). The vast majority of fit AML patients will undergo hematopoietic

stem cell transplantation (HSCT) after achieving a CR. However, 40% of these patients relapse after HSCT. Thus, refractory or relapsed

(r/r) AML is a very common scenario in AML and despite recent advances and new targeted therapies, the management of AML remains a challenge,

particularly in older adults ineligible for intensive therapies. According to the National Cancer Institute (NCI), the five-year survival

rate is about 35% in people under 60 years old, and 10% in people over 60 years old. Older people whose health is too poor for intensive

chemotherapy have a typical survival of five to ten months. AML accounts for approximately 1.8% of cancer deaths in the United States.

About

GTB-3550 TriKE® Clinical Trial

We

opened our GTB-3550 Phase 1 clinical trial in September 2019 and enrolled our first patient in January 2020. Patients with CD33+

malignancies (primary induction failure or relapsed AML with failure of one reinduction attempt or high-risk MDS progressed on two lines

of therapy) age 18 and older were eligible (ClinicalTrials.gov Identifier NCT03214666). The primary endpoint is to identify the

maximum tolerated dose (MTD) of GTB-3550 TriKE®. Correlative objectives include the number, phenotype, activation

status and function of NK cells and T cells. From January, 2020 until September, 2021 twelve patients received escalating doses of GTB-3550

in the Phase 1 trial. The results of this trial were presented at several conferences in 2021. To summarize, the therapy was overall

well tolerated and safe. There were no serious cases of cytokine release syndrome observed. Four of twelve patients had transient reductions

in bone marrow leukemic blast cells. Correlative studies showed activation, proliferation, and persistence of functionally active endogenous

NK cells. The results of our first generation GTB-3550 Phase 1 clinical trial support our plans to advance the next generation camelid

nanobody into the clinic.

The

Next Generation of Camelid Nanobody TriKE®s

Our

goal is to be a leader in immuno-oncology therapies targeting a broad range of indications including hematological malignancies and solid

tumors. A key element of our strategy includes introducing a next-generation camelid nanobody platform. Camelid antibodies (often referred

as nanobodies) are smaller than human immunoglobulin and consist of two heavy chains. These nanobodies have the potential to have greater

affinity to target antigens, potentially resulting in greater potency. GT Biopharma is utilizing this camelid antibody structure for

all its new TriKE® product candidates.

Generation

of humanized single-domain antibody targeting CD16 for incorporation into the TriKE® platform

To

develop second generation TriKE®s, we designed a new humanized CD16 engager derived from a single-domain antibody.

While scFvs consist of a heavy and a light variable chain joined by a linker, single-domain antibodies consist of a single variable heavy

chain capable of engaging without the need of a light chain counterpart (see figure below).

These

single-domain antibodies are thought to have certain attractive features for antibody engineering, including physical stability, ability

to bind deep grooves, and increased production yields, amongst others. Pre-clinical studies demonstrated increased NK cell activation

against CD33+ targets including NK cell degranulation (% CD107a+) and IFNg of the single-domain CD16 TriKE® (cam

16-wt15-33; GTB-3650) compared to the original TriKE® (scFv16-m 15-33; GTB-3550) (see figure below). These data

were published by Felices M et al (2020) in Cancer Immunol Res.

CD33+

HL60 Targets

GTB-3650

GTB-3650

is a CD33 targeted TriKE® which targets CD33 on the surface of myeloid leukemias. We are advancing GTB-3650

through preclinical studies and anticipate filing an Investigational New Drug (IND) for a Phase 1 clinical trial in the second

half of 2022. This study will target patients with relapsed/refractory AML and high grade MDS.

GTB-5550

GTB-5550 is a B7-H3 targeted TriKE®

which targets B7-H3 on the surface of advanced solid tumors. We are advancing GTB-5550 through preclinical studies and have

initiated a GMP manufacturing campaign in anticipation of filing an IND and initiating a Phase 1 clinical trial in the

second half of 2022 and the first half of 2023, respectively. This study will target patients with B7-H3 positive solid tumors.

Oncology

Markets

Acute

Myeloid Leukemia and Myelodysplastic Syndromes

AML

is a heterogeneous hematologic stem cell malignancy in adults with incidence rate of 4.3% per 100,000 populations. The median age at

the time of diagnosis is 68 years. AML is an aggressive disease and is fatal without anti-leukemic treatment. AML is the most common

form of adult leukemia in the U.S. These patients will require frontline therapy, usually chemotherapy including cytarabine and an anthracycline,

a therapy that has not changed in over 40 years. Myelodysplastic syndromes are a heterogeneous group of myeloid neoplasms characterized

by dysplastic features of erythroid/myeloid/megakaryocytic lineages, progressive bone marrow failure, a varying percentage of blast cells,

and enhanced risk to evolve into acute myeloid leukemia. It is estimated that over 10,000 new cases of MDS are diagnosed each year and

there are minimal treatment options; other estimates have put this number higher. In addition, the incidence of MDS is rising for unknown

reasons.

B7-H3

Positive Solid Tumors

The

B7-H3 protein, which functions as a checkpoint inhibitor, has been identified in many of the most common solid tumor cancers,

including but not limited to bladder, breast, cervical, colorectal, endometrial, esophageal, gastric, glioma, kidney, liver, lung, pancreatic,

prostate, head and neck cancer, and melanoma. In recent studies, B7-H3 has been identified as a critical promoter of tumor cell proliferation,

migration, invasion, epithelial-to-mesenchymal transition, cancer stemness and drug resistance. Because this protein does not seem to

be expressed in normal cells, this makes it an attractive target for therapeutic intervention.

Manufacturing

We

do not currently own or operate manufacturing facilities for the production of clinical or commercial quantities of any of our product

candidates. We rely on a third-party contract manufacturing operation to produce and/or test our compounds and expect to continue to

do so to meet the preclinical and clinical requirements of our potential product candidates as well as for our future commercial needs.

We do not have long-term commitments with a third-party product manufacturer. We require in our manufacturing and processing agreements

that third-party product manufacturers produce intermediates, active pharmaceutical ingredients, or API, and finished products

in accordance with the FDA’s current Good Manufacturing Practices (cGMP), and all other applicable laws and regulations.

We maintain confidentiality agreements with potential and existing manufacturers to protect our proprietary rights related to our drug

candidates.

Patents

and Trademarks

Immuno-oncology

platform

TriKE®

Patents

On

August 24, 2021, two patents were issued by the US Patent Office covering our pipeline of clinical and non-clinical product

candidates consisting of tri-specific killer engagers, or TriKE®s, designed to target natural killer, or NK, cells and

tumor or virus infected cells forming an immune synapse between the NK cell and the tumor cell thereby inducing NK cell activation at

that site. The patents broadly include TriKE®s that target the CD16 receptor, which includes the more potent camelid nanobody

sequence, an IL-15 activating domain, and any targeting domain.

University

of Minnesota License Agreements

2016 Exclusive Patent License Agreement

We are party to an exclusive worldwide license

agreement with the Regents of the University of Minnesota, (“UofMN”) to further develop and commercialize cancer therapies

using TriKE® technology developed by researchers at the University to target NK cells to cancer. Under the terms of the

2016 agreement, we received exclusive rights to conduct research and to develop, make, use, sell, and import TriKE® technology

worldwide for the treatment of any disease, state or condition in humans. We are responsible for obtaining all permits, licenses, authorizations,

registrations and regulatory approvals required or granted by any governmental authority anywhere in the world that is responsible for

the regulation of products such as the TriKE® technology, including without limitation the FDA and the European Agency

for the Evaluation of Medicinal Products in the European Union. Under the agreement, the University of Minnesota received an upfront

payment of $200,000, annual license maintenance fees of $100,000 beginning in 2021, 4% royalty fees (not to exceed 6% under subsequent

license agreements or amendments to this agreement), upon sale of a licensed product or a minimum annual royalty payment ranging from

$250,000 to $5.0 million. The agreement also includes certain milestone payments totaling $3.1 million, and one-time sales milestone

payments of $1.0 million upon reaching $250 million in gross sales and $5.0 million upon reaching $500 million in cumulative gross sales

of licensed products.

2021 Exclusive License Agreement

On March 26, 2021, we entered into an agreement

with the UofMN specific to the B7H3 targeted TriKE®. Under the agreement, the UofMN received an upfront license fee of

$20,000, and will receive annual license maintenance fees of $5,000 beginning in 2022, 2.5% to 5% royalty fees or minimum annual royalty

payments of $250,000 beginning in the first year after the first commercial sale of licensed product, and $2.0 million beginning in the

fifth year after the first commercial sale of licensed product. The agreement also includes certain milestone payments totaling $3.1

million and one-time sales milestone payments of $1.0 million upon reaching $250 million in gross sales, and $5.0 million upon reaching

$500 million in cumulative gross sales of licensed products. There is no double payment intended; if one of the milestone payments has

been paid under the 2016 agreement, no further payment is due for the corresponding milestone above.

Employees

At

the date of this Annual Report, we had eight

full-time employees. Many of our activities are outsourced to consultants who provide services to us on a project basis. As business

activities require and capital resources permit, we will hire additional employees to fulfill our company’s needs.

Form

and Year of Organization

In

1965, the corporate predecessor of GT Biopharma, Diagnostic Data, Inc., was incorporated in the State of California. Diagnostic

Data changed its incorporation to the State of Delaware in 1972, and changed its name to DDI Pharmaceuticals, Inc. in 1985. In

1994, DDI Pharmaceuticals merged with International BioClinical, Inc. and Bioxytech S.A. and changed its name to OXIS International,

Inc. On July 17, 2017, we amended our Certificate of Incorporation for the purpose of changing our name from Oxis International, Inc.

to GT Biopharma, Inc.

ITEM

1A. RISK FACTORS

Investing

in our common stock involves a high degree of risk. You should carefully consider the risks and uncertainties described below in addition

to the other information contained in this Annual Report on Form 10-K before deciding whether to invest in shares of our common

stock. If any of the following risks actually occur, our business, financial condition or operating results could be harmed. In that

case, the trading price of our common stock could decline and you may lose part or all of your investment. In the opinion of management,

the risks discussed below represent the material risks known to the company. Additional risks and uncertainties not currently known to

us or that we currently deem immaterial may also impair our business, financial condition and operating results and adversely affect

the market price of our common stock.

Risks

Related to Our Business

Our

business is at an early stage of development and we may not develop therapeutic products that can be commercialized.

Our

business is at an early stage of development. We do not have immune-oncology products in late stage clinical trials. We are still in

the early stages of identifying and conducting research on potential therapeutic products. Our potential therapeutic products will require

significant research and development and pre-clinical and clinical testing prior to regulatory approval in the United States and other

countries. We may not be able to obtain regulatory approvals, enter clinical trials for any of our product candidates, or commercialize

any products. Our product candidates may prove to have undesirable and unintended side effects or other characteristics adversely affecting

their safety, efficacy or cost effectiveness that could prevent or limit their use. Any product using any of our technology may fail

to provide the intended therapeutic benefits or achieve therapeutic benefits equal to or better than the standard of treatment at the

time of testing or production.

We

have a history of operating losses and we expect to continue to incur losses for the foreseeable future and we may never generate revenue

or achieve profitability.

During

the year ended December 31, 2021, the Company reported a net loss of $58.0 million and as of December 31, 2021, we had an accumulated

deficit of $653.6 million. We have not generated any significant revenue to date and are not profitable, and have incurred losses

in each year since our inception. We do not expect to generate any product sales or royalty revenues for the foreseeable future.

We expect to incur significant additional operating losses for the foreseeable future as we expand research and development and clinical

trial efforts.

Our

ability to achieve long-term profitability is dependent upon obtaining regulatory approvals for our products and successfully commercializing

our products alone or with third parties. However, our operations may not be profitable even if any of our products under development

are successfully developed and produced and thereafter commercialized. Even if we achieve profitability in the future, we may not be

able to sustain profitability in subsequent periods.

Even

if we succeed in commercializing one or more of our product candidates, we expect to continue to incur substantial research and development

and other expenditures to develop and market additional product candidates. The size of our future net losses will depend, in part, on

the rate of future growth of our expenses and our ability to generate revenue. Our prior losses and expected future losses have had and

will continue to have an adverse effect on our stockholders’ equity and working capital.

We

will need additional capital to conduct our operations and develop our products, and our ability to obtain the necessary funding is uncertain.

We

have used a significant amount of cash since inception to finance the continued development and testing of our product candidates, and

we expect to need substantial additional capital resources to develop our product candidates going forward and launch and commercialize

any product candidates for which we receive regulatory approval.

We

may not be successful in generating and/or maintaining operating cash flow, and the timing of our capital expenditures and other expenditures

may not result in cash sufficient to sustain our operations through the commercialization of our product candidates. If financing

is not sufficient and additional financing is not available or available only on terms that are detrimental to our long-term survival,

it could have a material adverse effect on our ability to continue to function. The timing and degree of any future capital requirements

will depend on many factors, including:

● scientific and clinical progress in our research and development programs;

● our progress with pre-clinical development and clinical trials;

● the time and costs involved in obtaining regulatory approvals;

● the number and type of product candidates that we pursue.

Additional

financing through strategic collaborations, public or private equity or debt financings or other financing sources may not be available

on acceptable terms, or at all. Additional equity financing could result in significant dilution to our stockholders, and any debt financings

will likely involve covenants restricting our business activities. Further, if we obtain additional funds through arrangements with collaborative partners, these arrangements may require us to

relinquish rights to some of our technologies, product candidates or products that we would otherwise seek to develop and commercialize

on our own.

If

sufficient capital is not available, we may be required to delay, reduce the scope of or eliminate one or more of our research or product

development initiatives, any of which could have a material adverse effect on our financial condition or business prospects.

Our research and development

costs could exceed our projections requiring us to significantly modify our planned operations.

Our

currently projected expenditures for 2022 include approximately $12 million to $14 million for research and development.

The actual cost of our programs could differ significantly from our current projections if we change our planned development process.

In the event that actual costs of our clinical program, or any of our other ongoing research activities, are significantly higher than

our current estimates, we may be required to significantly modify our planned level of operations.

The

successful development of any product candidate is highly uncertain. It is difficult to reasonably estimate or know the nature, timing

and costs of the efforts necessary to complete the development of, or the period in which material net cash inflows are expected to commence

from any product candidate, due to the numerous risks and uncertainties associated with developing drugs. Any failure to complete any

stage of the development of products in a timely manner could have a material adverse effect on our operations, financial position and

liquidity.

We

have identified material weaknesses in our internal controls over financial reporting and are working to remedy these weaknesses. If

we fail to maintain an effective system of internal control over financial reporting, we may not be able to accurately report our financial

results or prevent fraud. As a result, stockholders could lose confidence in our financial and other public reporting, which would harm

our business and the trading price of our common stock.

Effective

internal control over financial reporting is necessary for us to provide reliable financial reports and, together with adequate disclosure

controls and procedures, are designed to prevent fraud. Any failure to implement required new or improved controls, or difficulties encountered

in their implementation, could cause us to fail to meet our reporting obligations. Ineffective internal control could also cause investors

to lose confidence in our reported financial information, which could have a negative effect on the trading price of our common stock.

We

have identified material weaknesses in our internal control over financial reporting as a company, which have resulted in unauthorized

transactions involving our assets and common stock. As defined in Regulation 12b-2 under the Securities Exchange Act of 1934, or

the Exchange Act, a “material weakness” is a deficiency, or combination of deficiencies, in internal control over financial

reporting, such that there is a reasonable possibility that a material misstatement of our annual or interim consolidated financial statements

will not be prevented, or detected on a timely basis. Specifically, we determined that we had the following material weaknesses in our

internal control over financial reporting: (i) inadequate segregation of duties; (ii) risks of executive override; and (iii) insufficient

written policies and procedures for accounting and financial reporting with respect to the requirements and application of both generally

accepted accounting principles in the United States of America, or GAAP, and the U.S. Securities and Exchange Commission, or the SEC,

guidelines.

As

of the date of this Annual Report, we have remediated some of these material weaknesses. The company has taken measures to mitigate

the issues identified and implement a functional system of internal controls over financial reporting. Specifically, the Company has

engaged a forensic accountant to review the Company’s bank records, transactions with affiliates and/or related parties, expense

reimbursement practices and vendor payment practices. That review is ongoing. In addition, the Company’s Board of Directors previously

designated a Special Committee in August 2021 charged with, among other duties, evaluating the current compliance, compensation, operations

and personnel of the Company, and determining actions appropriate to address any deficiencies or inefficiencies identified through such

evaluation. Such measures include, but are not limited to the hiring of additional employees in its finance and accounting department;

preparation of risk-control matrices to identify key risks and develop and document policies to mitigate those risks; and identification

and documentation of standard operating procedures for key financial activities. The implementation of these initiatives may not fully

address any material weakness or other deficiencies that we may have in our internal control over financial reporting.

Even

if we develop effective internal control over financial reporting, such controls may become inadequate due to changes in conditions,

or the degree of compliance with such policies or procedures may deteriorate, which could result in the discovery of additional material

weaknesses and deficiencies. In any event, the process of determining whether our existing internal control over financial reporting

is compliant with Section 404 of the Sarbanes-Oxley Act, or Section 404, and sufficiently effective requires the investment of substantial

time and resources, including by certain members of our senior management. As a result, this process may divert internal resources and

take a significant amount of time and effort to complete. In addition, we cannot predict the outcome of this process and whether we will

need to implement remedial actions to establish effective controls over financial reporting. The determination of whether or

not our internal controls are sufficient and any remedial actions required could result in us incurring additional costs that we did

not anticipate, including the hiring of outside consultants. We may also fail to timely complete our evaluation, testing and any remediation

required to comply with Section 404.

We

are required, pursuant to Section 404, to furnish a report by management on, among other things, the effectiveness of our internal control

over financial reporting. However, for as long as we are a “smaller reporting company,” our independent registered public

accounting firm will not be required to attest to the effectiveness of our internal control over financial reporting pursuant to Section

404. While we could be a smaller reporting company for an indefinite amount of time, and thus relieved of the above-mentioned attestation

requirement, an independent assessment of the effectiveness of our internal control over financial reporting could detect problems that

our management’s assessment might not. Such undetected material weaknesses in our internal control over financial reporting could

lead to financial statement restatements and require us to incur the expense of remediation.

Our

intellectual property may be compromised.

Part

of our value going forward depends on the intellectual property rights that we have been and are acquiring. There may have been many

persons involved in the development of our intellectual property, and we may not be successful in obtaining the necessary rights from

all of them. It is possible that in the future, third parties may challenge our intellectual property rights. We may not be successful

in protecting our intellectual property rights. In either event, we may lose the value of our intellectual property, and if so, our business

prospects may suffer.

If

our efforts to protect the proprietary nature of the intellectual property related to our technologies are not adequate, we may not be

able to compete effectively in our market and our business would be harmed.

We

rely upon a combination of patents, trade secret protection and confidentiality agreements to protect the intellectual property related

to our technologies. Any disclosure to or misappropriation by third parties of our trade secret or other confidential information could

enable competitors to quickly duplicate or surpass our technological achievements, thus eroding any competitive advantage we may derive

from this information.

The

strength of patents in the biotechnology and pharmaceutical field involves complex legal and scientific questions and can be uncertain.

The patent applications we own or license may fail to result in issued patents in the United States or in foreign countries. Third parties

may challenge the validity, enforceability or scope of any issued patents we own or license or any applications that may be issued

as patents in the future, which may result in those patents being narrowed, invalidated or held unenforceable. Even if they are unchallenged,

our patents and patent applications may not adequately protect our intellectual property or prevent others from developing similar products

that do not fall within the scope of our patents. If the breadth or strength of protection provided by the patents we hold or pursue

is threatened, our ability to commercialize any product candidates with technology protected by those patents could be threatened. Further,

if we encounter delays in our clinical trials, the time during which we would have patent protection for any covered product

candidates that obtain regulatory approval would be reduced. Since patent applications in the United States and most other countries

are confidential for a period of time after filing, we cannot be certain at the time of filing that we are the first to file any patent

application related to our product candidates.

In

addition to the protection afforded by patents, we seek to rely on trade secret protection and confidentiality agreements to protect

proprietary know-how that is not patentable, processes for which patents are difficult to enforce and any other elements of our discovery

platform and drug development processes that involve proprietary know-how, information or technology that is not covered by patents or

not amenable to patent protection. Although we require all of our employees and certain consultants and advisors to assign inventions

to us, and all of our employees, consultants, advisors and any third parties who have access to our proprietary know-how, information

or technology to enter into confidentiality agreements, our trade secrets and other proprietary information may be disclosed or competitors

may otherwise gain access to such information or independently develop substantially equivalent information. Further, the laws of some

foreign countries do not protect proprietary rights to the same extent or in the same manner as the laws of the United States. As a result,

we may encounter significant difficulty in protecting and defending our intellectual property both in the United States and abroad. If

we are unable to prevent material disclosure of the trade secret intellectual property related to our technologies to third parties,

we may not be able to establish or maintain the competitive advantage that we believe is provided by such intellectual property, which

could materially adversely affect our market position and business and operational results.

Claims

that we infringe the intellectual property rights of others may prevent or delay our drug discovery and development efforts.

Our

research, development and commercialization activities, as well as any product candidates or products resulting from those activities,

may infringe or be accused of infringing a patent or other form of intellectual property under which we do not hold a license or other

rights. Third parties may assert that we are employing their proprietary technology without authorization. There may be third-party patents

of which we are currently unaware, with claims that cover the use or manufacture of our product candidates or the practice of our related

methods. Because patent applications can take many years to issue, there may be currently pending patent applications that may later

result in issued patents that our product candidates may infringe. In addition, third parties may obtain patents in the future and claim

that use of our technologies infringes one or more claims of these patents. If our activities or product candidates infringe the patents

or other intellectual property rights of third parties, the holders of such intellectual property rights may be able to block our ability

to commercialize such product candidates or practice our methods unless we obtain a license under the intellectual property rights or

until any applicable patents expire or are determined to be invalid or unenforceable.

Defense

of any intellectual property infringement claims against us, regardless of their merit, would involve substantial litigation expense

and would be a significant diversion of employee resources from our business. In the event of a successful claim of infringement against

us, we may have to pay substantial damages, obtain one or more licenses from third parties, limit our business to avoid the infringing

activities, pay royalties and/or redesign our infringing product candidates or methods, any or all of which may be impossible or require

substantial time and monetary expenditure. Further, if we were to seek a license from the third party holder of any applicable intellectual

property rights, we may not be able to obtain the applicable license rights when needed or on commercially reasonable terms, or at all.

The occurrence of any of the above events could prevent us from continuing to develop and commercialize one or more of our product candidates

and our business could materially suffer.

We

may desire, or be forced, to seek additional licenses to use intellectual property owned by third parties, and such licenses may not

be available on commercially reasonable terms or at all.

A

third party may hold intellectual property, including patent rights, that are important or necessary to the development of our product

candidates, in which case we would need to obtain a license from that third party or develop a different formulation of the product that

does not infringe upon the applicable intellectual property, which may not be possible. Additionally, we may identify product candidates

that we believe are promising and whose development and other intellectual property rights are held by third parties. In such a case,

we may desire to seek a license to pursue the development of those product candidates. Any license that we may desire to obtain or that

we may be forced to pursue may not be available when needed on commercially reasonable terms or at all. Any inability to secure a license

that we need or desire could have a material adverse effect on our business, financial condition and prospects.

The

patent protection covering some of our product candidates may be dependent on third parties, who may not effectively maintain that protection.

While

we expect that we will generally seek to gain the right to fully prosecute any patents covering product candidates we may in-license

from third-party owners, there may be instances when platform technology patents that cover our product candidates remain controlled

by our licensors. If any of our current or future licensing partners that retain the right to prosecute patents covering the product

candidates we license from them fail to appropriately maintain that patent protection, we may not be able to prevent competitors from

developing and selling competing products or practicing competing methods and our ability to generate revenue from any commercialization

of the affected product candidates may suffer.

We

may be involved in lawsuits to protect or enforce our patents or the patents of our licensors, which could be expensive, time-consuming

and unsuccessful.

Competitors

may infringe our patents or the patents of our current or potential licensors. To attempt to stop infringement or unauthorized use, we

may need to enforce one or more of our patents, which can be expensive and time-consuming and distract management. If we pursue any litigation,

a court may decide that a patent of ours or our licensor’s is not valid or is unenforceable, or may refuse to stop the other party

from using the relevant technology on the grounds that our patents do not cover the technology in question. Further, the legal systems

of certain countries, particularly certain developing countries, do not favor the enforcement of patents, which could reduce the likelihood

of success of any infringement proceeding we pursue in any such jurisdiction. An adverse result in any infringement litigation or defense

proceedings could put one or more of our patents at risk of being invalidated, held unenforceable, or interpreted narrowly and could

put our patent applications at risk of not issuing, which could limit our ability to exclude competitors from directly competing with

us in the applicable jurisdictions.

Interference

proceedings provoked by third parties or brought by the U.S. PTO may be necessary to determine the priority of inventions with respect

to our patents or patent applications or those of our licensors. An unfavorable outcome could require us to cease using the related technology

or to attempt to license rights to use it from the prevailing party. Our business could be harmed if the prevailing party does not offer

us a license on commercially reasonable terms, or at all. Litigation or interference proceedings may fail and, even if successful, may

result in substantial costs and distract our management and other employees.

If

we are unsuccessful in obtaining or maintaining patent protection for intellectual property in development, our business and competitive

position would be harmed.

We

are seeking patent protection for some of our technology and product candidates. Patent prosecution is a challenging process and is not

assured of success. If we are unable to secure patent protection for our technology and product candidates, our business may be adversely

impacted.

In

addition, issued patents and pending international applications require regular maintenance. Failure to maintain our portfolio may result

in loss of rights that may adversely impact our intellectual property rights, for example by rendering issued patents unenforceable or

by prematurely terminating pending international applications.

If

we are unable to protect the confidentiality of our trade secrets, our business and competitive position would be harmed.

In addition to seeking patents for some of our technology

and product candidates, we also rely on trade secrets, including unpatented know-how, technology and other proprietary information, to

maintain our competitive position. We currently, and expect in the future to continue to, seek to protect these trade secrets, in part,

by entering into confidentiality agreements with parties who have access to them, such as our employees, collaborators, contract manufacturers,