PD-1 (programmed cell death protein 1) is a negative regulator of immune activation that is considered a foundational target within the immuno-oncology market. In 2018, the Nobel Prize in Medicine was awarded for the establishment of PD-1 as a cancer immunotherapy target. Agenus has applied these scientific principles to create a therapy designed to treat cancer, AGEN2034.

AGEN2034 is a novel, fully human monoclonal immunoglobulin G4 (IgG4) designed to block PD-1 from interacting with its ligands PD-L1 and PD-L2.

AGEN2034 is clinically active in patients with advanced or refractory cancer.

In August 2021, Agenus announced the publication of results from a global Phase 2 clinical study of balstilimab monotherapy in recurrent/metastatic cervical cancer in the international peer reviewed journal Gynecologic Oncology. In the 140 evaluable patients, overall response rate (ORR) was 15%, disease control rate (DCR) was ~50% and the median duration of response was 15.4 months. In the 85 evaluable patients with PD-L1 positive tumors, an ORR of 20% was achieved.

Agenus controls worldwide rights to AGEN2034, except for certain South American rights, which are controlled by Recepta Biopharma, and Greater China rights, which are exclusively licensed to Betta Pharmaceuticals.

CTLA-4 (cytotoxic T-lymphocyte antigen-4), is a negative regulator of immune activation that is considered a foundational target within the immuno-oncology market. In 2018, the Nobel Prize in Medicine was awarded for the establishment of CTLA-4 as a cancer immunotherapy target. Agenus has applied these scientific findings to create a therapy designed to treat cancer, AGEN1884.

AGEN1884 is a fully humanized monoclonal antibody that activates the immune system to destroy cancer cells by blocking the interaction between CTLA-4 and its binding partners CD80 and CD86.

AGEN1884 is clinically active in patients with advanced or refractory cancer. In fact, we have seen a complete and durable response in a patient with refractory angiosarcoma. This patient was profiled in the news.

In September 2021, Agenus presented updated results from the Phase 2 trial evaluating zalifrelimab in combination with balstilimab in recurrent/metastatic cervical cancer at the ESMO Virtual Conference. In the 125 evaluable patients, overall response rate (ORR) was ~26%, and the median duration of response was not reached (median follow up of 19.4 months). In the 67 evaluable patients with PD-L1 positive tumors, an ORR of ~33% was achieved, expanding benefit seen with anti PD-1 therapy alone.

Agenus controls worldwide rights to AGEN1884, except for certain South American rights, which are controlled by Recepta Biopharma, and Greater China rights, which are exclusively licensed to Betta Pharmaceuticals.

Botensilimab (also known as AGEN1181) is a multipurpose, second-generation “Fc-engineered” anti-CTLA-4 antibody with enhanced tumor fighting abilities, designed to generate responses in a larger number of patients and improve immunogenicity.

The clinical performance of botensilimab has been consistent with its design. More than 100 patients have been treated to date in a Phase 1 study; Botensilimab is the first anti-CTLA-4 antibody to demonstrate clinical activity in 9 cold, treatment-resistant tumors as monotherapy and in combination with PD-1 (balstilimab). Below is a summary of the data presented at the SITC 2021 meeting:

Monotherapy activity:

• Four cases of confirmed objective response – first reported CTLA-4 monotherapy response in endometrial, pancreatic and PD1 r/r cervical
• Multiple responses in patients expressing the low affinity FcyRIIIA receptor (F/F), who are unlikely to respond to first generation CTLA-4

 Combination activity (botensilimab + balstilimab)

• CRC: 14 of 20 pts benefited from combo; 4 PRs, 10 SDs
• Ovarian: 5 of 9 patients benefited from combo; 3 PRs, 2 SDs
• Endometrial: 3 of 3 pts benefited from monotherapy and combo; 1 CR, 2 PRs
• Durability: Responses in this Phase 1 trial have been durable, with half lasting at least 24 weeks and the majority ongoing

Based on this data, multi-arm, randomized phase 2/3 trials investigating botensilimab as monotherapy and in combination with balstilimab in MSS-CRC and gynecological cancers (ovarian and MSS-endometrial cancer) are being initiated. The design of these trials may support a potential filing for full and/or accelerated approval based on the magnitude of benefit demonstrated in the studies.

Discovery of Botensilimab and its Mechanism of Action

Agenus scientists discovered a new mechanism of action in which a specialized domain of the antibody engages with receptors on other immune cells to significantly bolster antitumor immunity. This discovery was published in Cancer Cell.

To develop botensilimab, Agenus leveraged the above discovery to modify a part of the antibody known as the Fc region, which interacts with other immune cells to enhance antitumor immunity. In pre-clinical studies, this “Fc-engineered” antibody significantly improved the cross-talk between antigen presenting cells (APCs) and T cells. In cancer immunotherapy, such an interaction is necessary to mount a potent immune response against cancer.

Botensilimab (also known as AGEN1181) is a multipurpose, second-generation “Fc-engineered” anti-CTLA-4 antibody with enhanced tumor fighting abilities, designed to generate responses in a larger number of patients and improve immunogenicity.

The clinical performance of botensilimab has been consistent with its design. More than 100 patients have been treated to date in a Phase 1 study; Botensilimab is the first anti-CTLA-4 antibody to demonstrate clinical activity in 9 cold, treatment-resistant tumors as monotherapy and in combination with PD-1 (balstilimab). Below is a summary of the data presented at the SITC 2021 meeting:

Monotherapy activity:

• Four cases of confirmed objective response – first reported CTLA-4 monotherapy response in endometrial, pancreatic and PD1 r/r cervical
• Multiple responses in patients expressing the low affinity FcyRIIIA receptor (F/F), who are unlikely to respond to first generation CTLA-4

 Combination activity (botensilimab + balstilimab)

• CRC: 14 of 20 pts benefited from combo; 4 PRs, 10 SDs
• Ovarian: 5 of 9 patients benefited from combo; 3 PRs, 2 SDs
• Endometrial: 3 of 3 pts benefited from monotherapy and combo; 1 CR, 2 PRs
• Durability: Responses in this Phase 1 trial have been durable, with half lasting at least 24 weeks and the majority ongoing

Based on this data, multi-arm, randomized phase 2/3 trials investigating botensilimab as monotherapy and in combination with balstilimab in MSS-CRC and gynecological cancers (ovarian and MSS-endometrial cancer) are being initiated. The design of these trials may support a potential filing for full and/or accelerated approval based on the magnitude of benefit demonstrated in the studies.

Discovery of Botensilimab and its Mechanism of Action

Agenus scientists discovered a new mechanism of action in which a specialized domain of the antibody engages with receptors on other immune cells to significantly bolster antitumor immunity. This discovery was published in Cancer Cell.

To develop botensilimab, Agenus leveraged the above discovery to modify a part of the antibody known as the Fc region, which interacts with other immune cells to enhance antitumor immunity. In pre-clinical studies, this “Fc-engineered” antibody significantly improved the cross-talk between antigen presenting cells (APCs) and T cells. In cancer immunotherapy, such an interaction is necessary to mount a potent immune response against cancer.

Bispecific antibodies are engineered to simultaneously bind two different antigens. They can be used to tailor the binding dynamics and effector functions of antibodies to specific cell types. We are developing two bispecific antibodies based on highly innovative strategies to combat tumor escape mechanisms.

AGEN1423 combats two prominent resistance pathways for cancer immunotherapy. These pathways are present across many tumor types and are associated with poor responses to checkpoint blockade and other treatments. Notably, this agent has the potential to enhance the antitumor activity of myeloid cells, NK cells, T cells, and cancer associated fibroblasts.

CD137 (4-1BB) is a positive regulator of the immune system that is highly upregulated on activated T cells (adaptive immune cells) and NK cells (innate immune cells). The potential to dually target innate and adaptive immunity makes CD137 a highly attractive target for cancer immunotherapy. AGEN2373 is a fully human monoclonal antibody that boosts the immune response to cancer cells by enhancing CD137 co-stimulatory signaling in activated immune cells. Importantly, the unique binding properties of AGEN2373 are expected to limit its activity outside of the tumor site and mitigate toxicities that may be associated with systemic activation of CD137 in humans.

AGEN2373 is advancing in a clinical trial against solid tumors.

CD137 (4-1BB) is a positive regulator of the immune system that is highly upregulated on activated T cells (adaptive immune cells) and NK cells (innate immune cells). The potential to dually target innate and adaptive immunity makes CD137 a highly attractive target for cancer immunotherapy. AGEN2373 is a fully human monoclonal antibody that boosts the immune response to cancer cells by enhancing CD137 co-stimulatory signaling in activated immune cells. Importantly, the unique binding properties of AGEN2373 are expected to limit its activity outside of the tumor site and mitigate toxicities that may be associated with systemic activation of CD137 in humans.

AGEN2373 is advancing in a clinical trial against solid tumors.

TIGIT is a negative regulator of innate and adaptive immune responses. AGEN1327 is a fully human monoclonal antibody that boosts the immune response to cancer cells by blocking the interaction between TIGIT and its binding partner CD155. Moreover, AGEN1327 is one of our next-generation antibodies which has been “Fc engineered” to maximize antitumor activity (see AGEN1181). Therefore, we expect that AGEN1327 will bring clinical benefit above and beyond that of conventional anti-TIGIT antibodies. TIGIT signaling has also been identified as a key resistance mechanism to anti-PD-1 therapy, suggesting that AGEN1327 can address therapeutic resistance to anti-PD-1 therapy.

AGEN1777 is a first-in-class TIGIT bispecific which targets a major inhibitory receptor expressed on T and NK cells to improve anti-tumor activity.

TIGIT is a negative regulator of innate and adaptive immune responses. AGEN1777 is a first-in-class TIGIT bispecific which targets a major inhibitory receptor expressed on T and NK cells to improve anti-tumor activity.

AGEN1777 is advancing as monotherapy and in combination with a PD-1 inhibitor in a clinical trial against solid tumors.

GITR is an immune checkpoint agonist, one of a class of receptors that amplify the immune system’s response to cancer. GITR (glucocorticoid-induced TNFR-related protein) is a receptor expressed on select populations of T cells. Activation of GITR leads to a more powerful anti-tumor inflammatory response, increased production of inflammatory signaling molecules and increased resistance to immunosuppression.

Our GITR agonist INCAGN1876 is part of our global alliance with Incyte. The program is funded by Incyte with Agenus eligible for potential milestones and 15% royalties, subject to reduction for certain third party obligations.  GITR agonists selectively amplify an antigen-specific immune response in the context of cancer. We believe that antibodies targeting GITR will act synergistically with approved cancer therapies as well as with other checkpoint antibodies and cancer vaccines being developed.

OX40 (also known as CD134 and TNFRSF4), a member of the TNFR super-family, is an immune-response-enhancing receptor found on activated T cells. OX40 promotes proliferation of these activated T cells and prevents the immunosuppressive activity of inhibitory T cells. We believe that antibodies that activate OX40 may help increase immune system activity through both of these mechanisms. Furthermore, OX40 antibodies have the potential to work alone or in combination with other therapeutics. Our INCAGN1949 antibody targeting OX40 is part of our global alliance with Incyte. The program is funded by Incyte with Agenus eligible for potential milestones and 15% royalties, subject to reduction for certain third party obligations.

TIM-3 is a checkpoint receptor found on certain immune cells. TIM-3 stands for T-cell immunoglobulin and mucin domain-3. To prevent hyperactivation, natural ligands binding to TIM-3 reduce the activity of these immune cells. In some types of cancer, T cells express elevated levels of TIM-3, which results in excessive immune suppression. Blocking TIM-3 could stimulate immune responses and promote immune-mediated clearing of cancer cells. TIM-3 antibodies may have a role as a monotherapy and hold great potential in combination therapy, since they may help overcome resistance that patients may develop against other therapeutics. Our TIM-3 checkpoint inhibitor is part of our global alliance with Incyte. The program is funded by Incyte with Agenus eligible for potential milestones and royalties ranging from 6-12%, subject to reduction for certain third party obligations.

LAG-3 is a checkpoint protein expressed on the surface of certain cells of the immune system. LAG-3 (lymphocyte-activation gene 3) modulates signaling between immune cells and their targets. When LAG-3 is activated, the immune response is suppressed. Antibodies that block LAG-3 can block this inhibitory signal, thereby boosting the immune system’s response against cancer cells. LAG-3 acts synergistically with other checkpoint modulators. This suggests antibodies against LAG-3 may be valuable as combination therapies . This is why we believe our LAG-3 checkpoint inhibitor may have potential in both combination and monotherapy settings. Our LAG-3 checkpoint inhibitor is part of our global alliance with Incyte. The program is funded by Incyte with Agenus eligible for potential milestones and royalties ranging from 6-12%, subject to reduction for certain third party obligations.

At MiNK, Agenus’s cell therapy subsidiary, we are advancing a pipeline of unique allogeneic cell therapies not only designed to address the limitations of autologous cell therapies but also many of the potential challenges of allogeneic cell therapy approaches currently being pursued.

Our allogeneic iNKTs do not require any genetic manipulation and have been manufactured under GMP conditions and in significantly expanded quantities. Further, if approved they can be offered at a fraction of the cost of existing cell therapies. Our iNKTs can also be used in combination with our own immune checkpoint antibodies as well as an iNKT cell activating lipid ligand; both designed to improve patient response.

Our world-renowned scientists have published more than 100 peer-reviewed articles specifically in this field. The advantages of our iNKT platform are summarized in the table below.

*GVHD: Graft vs. host disease.
** iNKTs express a molecule known as invariant TCR (iTCR) at their cell surface. iTCRs are highly specific to iNKTs and are not expressed by normal tissue. In the theoretical event that iNKTs trigger severe adverse events in a patient, iTCR can be targeted with a specific antibody to kill iNKTs without killing healthy immune cells. AgenTus has IP rights over such an antibody iPSC/HSC = Induced Pluripotent Stem Cells/Hematopoietic stem cells.

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QS-21 STIMULON^™ ADJUVANT

Agenus’ proprietary QS-21 Stimulon™ is believed to be one of the most potent adjuvants known. QS-21 Stimulon™ is a saponin extracted from the bark of the Quillaja saponaria (soap bark) evergreen tree native to warm temperate central Chile and purified using Agenus’ proprietary process. The adjuvant has been widely studied in over 120 clinical trials involving approximately 50,000 healthy volunteers and patients, and has consistently demonstrated powerful immune responses and a favorable safety profile

QS-21 Stimulon^™ is a key component in several GSK vaccines, including the most efficacious shingles vaccine, Shingrix^®, which has demonstrated >90% efficacy, as well as the first ever malaria vaccine, Mosquirix^®. QS-21 Stimulon^™ improves a vaccine’s effectiveness by inducing strong antibody and cell-mediated immune responses. It also plays a key role by boosting immune response in older adults who often experience age-related decline in immunity. In October 2017, the U.S. Food and Drug Administration (FDA) granted marketing authorization to GSK for Shingrix^® for the prevention of shingles in adults aged 50 years and older. The Center for Disease Control and Prevention recently declared Shingrix^® as the preferred shingles vaccine for approximately 62 million eligible adults in the United States. As a result, Shingrix^® revenues have exceeded expectations, tripling analyst estimates for 2018, its first year of commercial sales. GSK has forecast that annual revenues will exceed $600M in 2018 – comparable to the $668M in revenues generated by Zostavax in 2017 after >10 years on the market. Additionally, in 2017, the World Health Organization announced that Mosquirix^® will be made available to select African countries as a prophylactic measure targeted for young children.

Adding QS-21 Stimulon^™ with our vaccines give us critical advantages:

• Mutation-targeting vaccines often impart CD4 “helper” T cell responses. QS-21 Stimulon^™ generates both CD4 helper and CD8 killer T cell responses;
• QS-21 Stimulon^™ activates the innate immune system which is a critical partner to the adaptive (T cell-based) immune response to cancer;
• In pre-clinical studies, the combination of HSP, peptides and QS-21 stimulates a potent memory response which is necessary for vaccine efficacy.

In September 2015, Agenus partially monetized its potential royalty stream from GSK through a $100M non-dilutive royalty transaction with an investor group led by Oberland Capital.  In January 2018, Agenus repurchased the obligation from Oberland and sold the royalty stream outright to HealthCare Royalty Partners.