Immune checkpoint inhibitors, and other checkpoint antibodies that modulate the immune system, are revolutionizing cancer treatment and achieving curative outcomes in a number of cancers that were incurable only a few years ago.
Immune checkpoints are molecules that regulate immune response against pathogens that invade the body. Two classes of such checkpoint targets include:
- inhibitory checkpoints that help suppress an immune response in order to prevent excessive immune response resulting in undesired inflammation and/or auto-immunity, and
- stimulatory checkpoints that can enhance or amplify an antigen-specific immune response.
Cancer cells often evade immune detection by upregulating the expression of the inhibitory class of immune checkpoints. Thus therapeutic antibodies targeting checkpoints to help defeat cancer can work by two mechanisms: blocking, or neutralizing the inhibitory checkpoints that cancer cells use to escape immune attack, and/or empowering the immune system via the stimulatory checkpoints to help detect and eliminate cancer cells.
The early entrants’ success (e.g. targeting PD-1 and CTLA-4) in the treatment of cancers has sparked a high level of activity to create and develop clinically relevant checkpoint antibodies. But success has been irregular since individual checkpoint antibodies do not work consistently in all patients and/or cancers. We believe an integrated multidisciplinary approach will be needed because the future of cancer therapy will be based on the ability to identify subpopulations of patients that are likely to best respond to specific immuno-oncology agents or combinations. Our broad portfolio is uniquely positioned to bring these combination treatments to patients.
Checkpoint Development Programs
Agenus has a portfolio of more than 10 antibodies that target both foundational inhibitory checkpoints, such as CTLA-4 and PD-1, as well as novel, cutting-edge targets that we feel could provide exciting opportunities as research continues to emerge on their potential. In addition to CTLA-4 and PD-1 our initial disclosed targets include GITR, OX40, TIM-3 and LAG-3. We also have many undisclosed checkpoint targets. Lead candidates for our CTLA-4, GITR, OX40 and PD-1 programs were discovered during an earlier collaboration with Ludwig Cancer Research.
CTLA-4 (cytotoxic T-lymphocyte antigen-4) is a negative regulator of immune (T-cell) activation. AGEN1884, a CTLA-4 antagonist, is a fully human monoclonal antibody that works to activate the immune system by blocking CTLA-4. Inhibiting CTLA-4 has been shown to augment immune activation and enables the immune system to function properly to recognize and destroy cancer cells. CTLA-4 was the earliest checkpoint target to be identified and validated. Anti-CTLA-4 antibodies have been highly efficacious in treating cancer with curative results in some patients for whom standard of care has proven unsuccessful. Recent clinical data also suggests that anti-CTLA-4 antibodies are emerging as a central component of combination immunotherapeutic regimens for fighting cancer.
In June of 2016 at ASCO, we witnessed a dramatic validation of the clinical benefit of combination approaches, most specifically the importance of targeting CTLA-4 as the backbone of these combination strategies with prominence. Regimens involving lower and less frequent dosing of CTLA-4 antibody in combination with PD-1 inhibitors yielded a more pronounced clinical efficacy than either agent alone. Importantly, this was achieved without the added toxicity. Most experts now believe that the combination of CTLA-4 antibodies with PD-1 blockade using a tolerable dosing regimen is going to remain as a foundational immuno-oncology regimen that it was originally thought to be.
In April, 2016, we dosed the first patient in our Phase 1 clinical trial of AGEN1884, an anti-CTLA-4 checkpoint antibody. CTLA-4 is considered a foundational checkpoint within the immuno-oncology market. The open-label, multicenter trial in patients with advanced or refractory cancer is designed to evaluate the safety of AGEN1884 and determine the estimated maximum tolerated dose. Agenus also has a second antibody targeting CTLA-4 in preclinical development.
Having a proprietary CTLA-4 checkpoint inhibitor such as AGEN1884 gives us the ability to enter the field with a distinct and potentially more potent inhibitor. Just as important, having AGEN1884 allows us to test multiple combinations with other immunotherapies on our own. Combination agents suitable to combine with AGEN1884 could include other checkpoint modulators, vaccines and adjuvants. Agenus controls worldwide rights to AGEN1884, except for certain South American rights, which are controlled by Recepta Biopharma.
Like CTLA-4, PD-1 is another established checkpoint target. Blocking PD-1 is a known and very powerful way to “release the brakes” and let the immune system do its job and eliminate tumor cells. PD-1 (programmed cell death protein 1) is expressed on activated T cells and blocking it with checkpoint antibodies has been shown to be efficacious and sometimes curative in melanoma and lung cancer patients. As with CTLA-4, products targeting PD-1 have had great success treating cancer patients and may emerge as a central component of combination immunotherapeutic regimens for fighting cancer. Agenus controls worldwide rights to its PD-1 checkpoint inhibitors except for certain South American rights which are controlled by Recepta Biopharma.
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 royalties at a flat 15%. GITR agonists selectively amplify an antigen-specific immune response in the context of cancer. We believe that antibodies targeting GITR will act synergistically with existing cancer therapies as well as with other checkpoint antibodies and cancer vaccines. INCAGN1876 entered clinical trials in 2016.
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. Combining with another agonist checkpoint antibody, which provides different, yet complementary signaling attributes may further augment anti-tumor responses. 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 royalties at a flat 15%. INCAGN1949 entered clinical trials in 2016.
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%.
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%.