Vol. 3 · Issue 16 · August 11, 2020

Our Anti-CTLA-4s in Cervical Cancer and BeyondNew efficacy data with Agenus’ anti-CTLA-4 antibodies:

Zalifrelimab (first-gen) & AGEN1181 (next-gen multipurpose)

have suggested several reasons why this resistance occurs. One of these is up-regulation of other immune checkpoint pathways like CTLA-41. Given this observation, we are evaluating zalifrelimab as monotherapy in PD-1 refractory patients. We have already observed 3 partial responses across aggressive cancers such as angiosarcoma. Thirteen patients also have stable disease for >6 months, meaning that disease progression has been stopped (see table below).

Phase Overall Response Cancer Type

Ph1 (solid tumors) 1 CR; 4 SDs Angiosarcoma, other

solid tumors

Ph2 (PD-1 refractory) 3 PRs; 13 SDs Angiosarcoma, SCCHN,

Neuroendocrine

CTLA-4 has always been a central target for immuno-oncology. The first checkpoint antibody to ever be approved blocked CTLA-4. Its impact on advanced melanoma patients was practice changing. At the time of its approval in 2011, it was the first effective FDA-approved therapy for these patients in more than a decade. Since then, the I-O market has significantly expanded with the approval of a number of PD-1/PD-L1 antibodies. While they have been a spectacular commercial success, few patients sustain long term benefit from the currently-approved PD-1/PD-L1 antibodies. Therefore, CTLA-4 blockade remains central, as it has proven to increase anti-PD-1 benefit up to three-fold across ~15 tumor types (see Figure 1). New clinical data also suggest that CTLA-4 blockade significantly extends the duration of responses and overall survival in patients with aggressive cancers. CTLA-4 + PD-1/PD-L1 is the only approved I-O + I-O combination to date. It is currently approved in 6 settings. This market is still steadily growing; combined sales of CTLA-4 and PD-1 antibodies are expected to exceed $50B by 2025. Our intent is to deliver curative treatments to cancer patients while we participate in this significant market in a meaningful way. To this end, we are advancing two CTLA-4 antibody programs: zalifrelimab (first-generation) and AGEN1181 (next-generation), as monotherapy and in combination with our PD-1 antibody, balstilimab.

Zalifrelimab monotherapy: New data suggest benefit for patients who don’t effectively respond to PD-1 antibodiesAs mentioned earlier, the majority of patients do not respond to PD-1 blockade or experience subsequent relapse. Recent studies

During our R&D call last week, Dr. Bree Wilky, the Director of Sarcoma Translational Research at the University of Colorado, specifically discussed the promising benefits of zalifrelimab monotherapy in angiosarcoma. Angiosarcoma is a rare and highly aggressive form of soft tissue sarcoma. It has a high rate of local recurrence and metastasis. Overall survival can be as low as 6 months2. Doxorubicin is often the treatment of choice, and it was approved ~40 years ago. There is thus a large unmet need for effective treatments for these patients. With zalifrelimab monotherapy, we have now seen 2 responders (1 CR, 1 PR) in early clinical trials. Importantly, Dr. Wilky noted that the first angiosarcoma patient who had a complete response to zalifrelimab has been in remission for 4 years with no sign of cancer (see Figure 2). Thus, we believe that zalifrelimab monotherapy has the potential to cure some patients with this deadly cancer.

Based on this proof of concept, we have launched a Phase 2 study with Dr. Wilky to explore the combination of zalifrelimab and balstilimab with standard of care (doxorubicin) in soft tissue sarcomas. Doxorubicin is expected to induce cell death and expose neoantigens. This boost in tumor immunogenicity is expected to synergize well with CTLA-4 and PD-1 blockade. There are over 13,000 new cases and 5,000 deaths from soft tissue sarcomas in the US every year3. The incidence in Europe and China is almost double and triple this number respectively4. We are also preparing to launch a study of zalifrelimab and balstilimab specifically in angiosarcoma, which could potentially lead towards an opportunity for an accelerated approval. We look forward to continuing to work with Dr. Wilky to advance our therapies in this important area of unmet need.

Forward-Looking Statements: This Agenus Newsletter includes forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws, including statements regarding Agenus’ clinical development and regulatory plans and timelines, and the anticipated therapeutic and commercial potential of Agenus’ antibodies. These statements are subject to risks and uncertainties, including those described in our SEC filings.

Figure 1: Addition of CTLA-4 improves responses to PD-1 in solid tumors.

Vol. 3 · Issue 16 · August 11, 2020Our Anti-CTLA-4s in Cervical Cancer and Beyond •

Balstilimab +/- Zalifrelimab: significant commercial potential targeting cancers beyond cervical Agenus has also developed its own PD-1, balstilimab. Balstilimab has shown benefit for patients alone and in combination with zalifrelimab in clinical trials. We have combined balstilimab with zalifrelimab in various cancers across hundreds of patients. We have fully enrolled our Phase 2 study evaluating this combination in second line cervical cancer. Keytruda is the only I-O agent approved in this setting. However, not all patients are eligible to receive Keytruda. Its utility is restricted to patients whose tumors express the protein PD-L1. Even in this limited population, only about 14% of patients respond to therapy. With our combination, we have observed improved and longer-term responses in all cervical cancer patients. In patients with squamous cell carcinoma of the cervix (about 70% of all cervical cancers), we have seen a near doubling of response rates. Importantly, our combination has shown benefit regardless of the patient’s PD-L1 expression status. The same is true for balstilimab monotherapy; we observe a response rate of 14% among all cervical cancer patients, regardless of their PD-L1 expression status. Thus, our agents could represent potential best-in-class treatment options for ALL metastatic cervical cancer patients who have stopped responding to previous treatments. We

expect to initiate BLA submission for balstilimab monotherapy this quarter. If approved, balstilimab is targeted for our first commercial launch with second-line cervical cancer which affects ~10,000 patients in the US.

We have also reported clinical activity with our combination in other cancer types such as ovarian cancer, breast cancer and sarcoma. These are cancer types where the efficacy of CTLA-4 blockade has been previously validated (see Figure 1). Thus, our agents appear to be performing as expected of their class. We are looking to expand their footprint to other large indications where CTLA-4 + PD-1 antibodies have secured prior approval, such as melanoma, NSCLC and RCC. We are evaluating opportunities to drive broader use of our agents via inclusion in NCCN guidelines. A 5-10% share in these cancers alone could translate into a $1B+ market opportunity.

Antibody design: The next step in pursuing CTLA-4 as an important cancer target A key element in maximizing benefit of CTLA-4 blockade for patients is antibody design, specifically optimization of its structure. Amino acids are the building blocks of any antibody. Variation in the building blocks used gives rise to different types of antibodies such as IgG1, IgG2 etc. In 2018, we published a study evaluating functional differences between IgG2 and IgG1 anti-CTLA-4 antibodies. The comparison demonstrated that an IgG1 backbone is generally superior in mediating target cell killing for anti-CTLA-4 antibodies. Based on this finding, we are advancing development of a first-generation CTLA-4 antibody (zalifrelimab) with an IgG1 backbone. This is a proven antibody format given Yervoy®, the only approved CTLA-4 antibody, also has an IgG1 structure. We expect our rational antibody design to reduce risks in our clinical trial outcomes. This puts us in a favorable position to penetrate this large $50B market.

Although we have seen meaningful clinical efficacy with first-generation CTLA-4 agents, we are seeking to broaden the impact of targeting this key pathway. To that end, we have developed a next-generation CTLA-4 antibody (AGEN1181). Our scientists made the novel discovery in 2018 that the efficacy and therapeutic reach of a CTLA-4 antibody could be significantly enhanced by introducing specific mutations in the IgG1 backbone. AGEN1181 is thus designed to perform substantially better than its first generation competitors, which is reflected in very exciting early clinical data. Its design properties allow it to benefit 3X patients compared to first generation agents. This gives us the opportunity to substantially expand what is already a multi-billion dollar market. While zalifrelimab provides us the opportunity to take advantage of the current I-O market, AGEN1181 can potentially go much further than this and radically transform the space.

Figure 2: Complete response to zalifrelimab in refractory angiosarcoma.

Figure 3: Balstilimab +/- Zalifrelimab: $1B+ potential with expanded use.

Indication2024 US Sales

Estimate 5% Share 10% Share

Non-small cell lung cancer (NSCLC)

$8.2B $410M $820M

Melanoma $3.2B $160M $320M

Renal cell carcinoma (RCC)

$1.9B $95M $190M

Total $13.3B $0.7B $1.3B

Forward-Looking Statements: This Agenus Newsletter includes forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws, including statements regarding Agenus’ clinical development and regulatory plans and timelines, and the anticipated therapeutic and commercial potential of Agenus’ antibodies. These statements are subject to risks and uncertainties, including those described in our SEC filings.

Vol. 3 · Issue 16 · August 11, 2020Our Anti-CTLA-4s in Cervical Cancer and Beyond •

We intend to advance AGEN1181 with accelerated approval strategies in highly prevalent cancers where no active treatments exist. These include PD-1 refractory NSCLC, melanoma, and MSS tumors such as endometrial and colorectal cancers, representing over 40,000 eligible patients in the US alone. While these cancers typically do not respond to immunotherapies, we have seen clinical responses and benefit with AGEN1181. Advancing AGEN1181 in these settings currently underserved by immunotherapies could significantly expand the current $50B PD-1/CTLA-4 market.

To this point, a previous partial responder to low dose AGEN1181 + balstilimab with MSS-endometrial cancer has now achieved a complete response by PET scan. This is the second complete response to AGEN1181 in our Phase 1 study. One of the most notable experts in the I-O field, Dr. Charles Drake, Professor and Co-Director of Cancer Immunotherapy Programs at New York Presbyterian and Columbia University Herbert Irving Comprehensive Cancer Center, has said these signals are highly noteworthy in an early Phase 1 study.

Historic data from the CTLA-4 drug class allow us to place these data in context. In trials spanning over 1,000 patients across 10 different cancers, excluding melanoma, only 4 complete responses have been reported with Yervoy® monotherapy. While these responses were only observed at high doses of 3 mg/kg or 10 mg/kg of Yervoy®, responses with AGEN1181 were observed at doses of 1mg/kg or lower. Our trial will continue to evaluate higher doses of AGEN1181 to improve therapeutic benefit, as we have not yet reached a dose-limiting toxicity.

As discussed earlier, we have designed AGEN1181 to expand therapeutic benefit to 3X patients vs. first-generation CTLA-4 agents. This is because its antibody structure has the ability to also engage the immune system in patients who express a genetic polymorphism. First generation agents such as Yervoy® are unable to do this effectively, reducing their clinical benefit. In fact, patients who have responded to this AGEN1181 harbor this genetic polymorphism. This suggests that AGEN1181 is performing as designed to benefit these patients. Addressing this

large patient population who may not be responding to Yervoy® could substantially expand the size of the current $50B CTLA-4/PD-1 market.

During our R&D call last week, Dr. Charles Drake also discussed how the Fc backbone of AGEN1181 confers additional important benefits such as improved Treg depletion and safety. Indeed, we reported at ASCO that we have not observed any neuroendocrine toxicities with AGEN1181. This is a debilitating, irreversible adverse event that affects ~10-15% of patients treated with ipilimumab.

We have carefully designed our portfolio of CTLA-4 and PD-1 antibodies to deliver the best possible outcome to cancer patients: durable efficacy balanced with a tolerable safety profile. We intend to expand our footprint in multiple cancers to unlock blockbuster revenue potential from these agents. We look forward to providing you updates on our programs and anticipate presenting on up to 5 programs before the end of this year.

References:1. Koyama et al., Nat Commun. 2016 Feb 17;7:105012. Cao et al., Am J Cancer Res. 2019; 9(11): 2303–2313

3. https://www.cancer.org/cancer/soft-tissue-sarcoma/about/key-statistics.html4. Yang et al. Cancer Biol Med 2019

AGEN1181: Potential to expand and transform the current I-O market

Forward-Looking Statements: This Agenus Newsletter includes forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws, including statements regarding Agenus’ clinical development and regulatory plans and timelines, and the anticipated therapeutic and commercial potential of Agenus’ antibodies. These statements are subject to risks and uncertainties, including those described in our SEC filings.