Title:

Overcoming the inhibitory FcyRIIB barrier unlocks Fc-dependent activity of human anti-CTLA-4 antibodies

Abstract:

While antibodies targeting CTLA-4 were developed to block inhibitory signals in T cells, studies in mouse models demonstrated that Fc-dependent mechanisms, including depletion of tumor-infiltrating regulatory T cells (Tregs), are required for their complete antitumor activity. However, the two clinically available antibodies Ipilimumab and Tremelimumab do not show substantial Fc-dependent activity in cancer patients, which may limit their therapeutic efficacy.

Here, we investigate the mechanisms restraining the Fc-dependent activity of fully human anti-CTLA-4 antibodies in a novel humanized mouse model expressing both human CTLA-4 and human Fcγ receptors (FcγRs).

As observed in cancer patients, Ipilimumab and Tremelimumab were limited in their capacity to deplete tumor-infiltrating Tregs in humanized CTLA-4/FcγR mice, indicative of poor Fc effector function. We found that FcyRIIB, the inhibitory Fc receptor, was highly expressed in both murine and human tumors, acting as a potential barrier to Fc-dependent responses. Antibody-based blocking of FcyRIIB unlocked the Treg-depleting capacity of Ipilimumab and unleashed its antitumor activity. Alternatively, Fc-engineering of Ipilimumab to enhance binding to activating FcyRs while limiting binding to FcyRIIB significantly increased Treg depletion and antitumor activity. We obtained similar results with a Fc-optimized antibody targeting CCR8, a chemokine receptor selectively expressed on tumor-infiltrating Tregs.

Our results define FcyRIIB as a major barrier limiting the Fc-dependent activity of human anti-CTLA-4 antibodies in the tumor microenvironment and support the use of humanized mouse models to characterize the in vivo activity of therapeutic human antibodies.

Biography:

My name is Lucas Blanchard, I am 28 and I come from France. I did my PhD in the city of Toulouse in the laboratory of Dr. Jean-Philippe Girard (Institute of Pharmacology and Structural Biology). My PhD studies have mainly focused on understanding the mechanisms that control lymphocyte trafficking into tumors and examining how these processes could be harnessed to improve cancer immunotherapy. Since April 2023, I live in New York and work as a postdoctoral associate in the laboratory of Dr. Jeffrey Ravetch at the Rockefeller University. I wish to benefit from the unique expertise of the group in the development and engineering of therapeutic antibodies. Under the mentorship of Dr. Ravetch, my projects focus on understanding the mechanisms of action of Fc-engineered antibodies targeting various immune pathways, including CTLA-4 and CD40. The main objectives of these projects are to provide mechanistic insights on the activity of these novel cancer immunotherapies and to define how they could enhance the sensitivity to PD-1/PD-L1 immune checkpoint blockade. My long-term research goal is to become an independent scientist conducting projects aiming to better understand the immune response to cancer, to characterize the mechanisms modulating the efficacy of cancer immunotherapy and to develop novel therapeutic strategies that could bring the benefits of cancer immunotherapy to more patients.