Vol. 3 Issue 05 · Mar 10, 2020

AGEN1181 – Designed to benefit more patients with cancer

AGEN1181 goes beyond a standard anti-CTLA-4 with new features designed to increase tumor killing

The Nobel-winning discovery of an anti-CTLA-4 agent was a critically important milestone in the quest to CURE CANCER. An anti-CTLA-4 antibody helps activate T cells to help them do their cancer-killing job better. The benefit to some patients has been profound, and we now see long-term survival in previously incurable cancers, particularly in stage 4 melanoma. Importantly, combining anti-CTLA-4 with anti PD-1 antibodies expand benefits to even more patients. In some cases, this combination doubles response rates. Despite these advancements, which include the use of combinations with standard of care, only a fraction of patients experiences long term benefits and cures.

At IO 360°, Dr. Buell discussed Agenus’ next generation anti-CTLA-4 antibody, AGEN1181, which engages the immune system in new and different ways. AGEN1181 has already demonstrated early and exciting clinical activity.

The Year of Clinical Data

*AGEN1181 – more clinical responses coming through*Early data from our Phase 1 trial suggest that AGEN1181 could be a breakthrough in IO treatment. Several of the patients who were treated with AGEN1181 in our phase 1 dose escalation trial are showing clinical responses including:

1. A complete response in an endometrial cancer patient who had exhausted all treatment options including pembrolizumab. This was discussed at our Investor Day.

2. New partial responses in patients who were treated with AGEN1181 plus our anti-PD-1 antibody. These are new data.

3. Majority of evaluable patients experience disease stabilization after having progressed on prior treatments.

We expect updated clinical data from this trial to be presented at an upcoming cancer conference.

Agenus’ Novel Molecules Highlighted at Immuno-Oncology 360°

Synergistic Portfolio to Kill Cancer

On February 27th, Agenus’ President and COO, Dr. Jennifer Buell, joined thought leaders and experts in immuno-oncology (IO) at IO 360°, where science and business communities come together to discuss the latest developments. Dr. Buell joined Dr. Jeffrey Bockman of Cello Health BioConsulting, Dr. Chuck Drake of Columbia University, Asthika Goonewardene of SunTrust Robinson Humphrey, Michael King Jr. of Fortress Biotech, and Dr. Emmett Schmidt of Merck in a panel discussing “What Do Next Generation of Immunotherapies Need to Move the Needle?” In this issue, we highlight examples of how Agenus is moving the needle with its innovative pipeline of IO agents.

Can a ~$30B global immuno-oncology market grow? Agenus has amassed a portfolio of more than 13 molecules in the clinic*, both proprietary and partnered, as well as many more in discovery to expose and kill cancer. Our most advanced assets, zalifrelimab (anti-CTLA-4) and balstilimab (anti-PD-1), are expected to reach the market in 2021 in 2L cervical cancer, with an estimated market of $165M in cervical cancer. We believe these assets have the potential to expand beyond 2L cervical cancer and can grow and potentially cannibalize ~30% of the current overall market. Our approach will include the addition of our next generation, novel multi-T cell engager, AGEN1181. This molecule is designed to expand the benefit of anti-CTLA-4 to more than 60% of patients [from the current 20%]. This molecule has the potential to be a superior monotherapy, but importantly, a superior combination partner for our anti-PD-1. This will enable Agenus to take advantage of the most profitable and growing global market in oncology expected to reach $50B1 in 2025.

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 the market potential of our assets in 2L cervical cancer and beyond, the anticipated benefits of unapproved clinical candidates, including balstilimab, zalifrelimab, AGEN1181, AGEN1223 and GS-1423, plans for presentation of additional clinical data and anticipated IND filings. These statements are subject to risks and uncertainties, including those described in our SEC filings.

Vol. 3 Issue 05 · Mar 10, 2020The Year of Clinical Data •

Why AGEN1181 clinical responses are unique among other IO treatmentsPatients responding to AGEN1181 had genetic features that made them unlikely to respond. Yet, the fact that they responded to AGEN1181 speaks to the unique features of our multi-immune cell engaging agent and indicates early signals of responses in broad patient indications.

These data suggest that we may have overcome some of the limitations of existing I-O agents. Our inventors intended to improve a T cell’s ability to see a cancer’s molecular fingerprint so that the immune system recognizes other cancer cells throughout the body and KILL. AGEN1181 is also designed to combat immune suppression to enable T cells continue to KILL. Finally, this molecule is designed to benefit the additional 40% of patients who have a genetic marker that render them less likely to respond to first generation anti-CTLA-4. Importantly, our early data show the first few responders in our trial exhibited this genetic marker. Learn more about this special molecule from Dr. Dhan Chand, our Head of Drug Discovery, from

our Research and Development Day.

Creating an environment that is hostile to cancer

Our molecules are designed to alter the microenvironment that favors cancer’s growth

An optimally functioning immune system is designed to allow the elimination of disease with the appropriate checks and controls to protect healthy cells. In a cancer patient, these systems are disrupted. Regulatory immune cells (i.e. Tregs) protect the body’s healthy cells from immune attack. Depleting regulatory T cells can help fight cancer but may also cause side effects by destroying healthy cells.

Agenus found a solution to this problem. Our scientists identified a way to specifically target these regulatory (immune suppressive) cells, present in the tumor microenvironment. AGEN1223 targets hallmark receptors which are specific to Tregs in the tumor microenvironment

Note: This patent with metastatic endometrial cancer has the FcγRIIIA F/F low-affinity phenotype that is associated with poor outcomes with many types of immunotherapy, especially first generation anti-CTLA-4. The patient had a complete response following treatment with our next-generation anti-CTLA-4 AGEN1181. Source: Agenus Investor Day presentation.

Metastatic Endometrial Cancer: Confirmed Complete Response

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 the market potential of our assets in 2L cervical cancer and beyond, the anticipated benefits of unapproved clinical candidates, including balstilimab, zalifrelimab, AGEN1181, AGEN1223 and GS-1423, plans for presentation of additional clinical data and anticipated IND filings. These statements are subject to risks and uncertainties, including those described in our SEC filings.

Reference: 1) Cowen Equity Research. PD-(L)1 Market Model Update: Continued Growth into 2025. December 2019

Note: *proprietary and partnered programs

and is designed to target and deplete immune suppressive Tregs ONLY in the tumor microenvironment. In other words, this molecule is designed to bring an anti-cancer benefit and limit toxic side effects.

Tumors also escape the immune system by taking advantage of survival pathways. We created a molecule (now GS-1423) which blocks an important escape pathway. Specifically, in the tumor microenvironment, there is high expression of adenosine and TGFβ, which together cause broad immune suppression resulting in resistance to current therapies. Adenosine is generated by CD73, a well-known target on tumor cells. Agenus scientists observed that TGFβ also drives the expression of CD73. This bi-functional molecule blocks CD73 and prevents the generation of adenosine in the tumor microenvironment and neutralizes all forms of TGFβ.

Speed to innovationThe ability to go from an idea to an IND in less than two years is key to designing optimal solutions in real-time to address cancer biology.

Agenus’ next wave of innovation involves going beyond the T cell, addressing mechanisms of resistance and relapse to current therapies, and conditioning the tumor microenvironment for improved response to immune therapies. Agenus advanced three new molecules this year into the clinic that address this and we expect to file 3 additional INDs this year.