Abstract 1543: Discovery of CCR8 Antibodies Targeting Regulatory T Cells to Enable Tumor Sensitization

Regulatory T (Treg) cells in the tumor microenvironment have an immune suppressive function, and their presence is associated with poor prognosis. Depletion of Treg cells may be a mechanism to sensitize tumors and represents a novel strategy for cancer immunotherapy. High expression of chemokine receptor CCR8 has been found in Treg cells in microenvironments of numerous tumors but not on Treg cells in systemic lymphoid tissues. The ability to selectively kill Treg cells in tumor environments may provide an opportunity for therapy that leaves Treg function intact elsewhere in the body where they normally mediate tolerance to self-antigen. We sought to identify CCR8 antibodies for therapeutics and designed an antibody discovery strategy to address the challenges of this target. CCR8 is a member of the G protein-coupled receptor (GPCR) family. Like many GPCRs, CCR8 is a valuable therapeutic target but is challenging to target using antibodies due to its poor expression, membrane-dependent structure, small extracellular regions, and poor immunogenicity due to sequence conservation. We developed an antibody discovery platform (MPS) that specifically addresses each of these challenges through use of advanced immunization techniques and evolutionarily divergent host species (chickens) for robust immune responses against conserved targets. We extensively engineered CCR8 antigen to enable high expression for immunization. When sufficient antibody diversity using our standard immunization techniques was not obtained, we developed mRNA immunization techniques for this program. Using these approaches, we were able to identify a panel of high-affinity antibodies that bind in the nanomolar or subnanomolar range with high specificity. We will present data from our antibody discovery campaign including mRNA immunization, binding profiles, GPCR functional data, and the ability of the antibodies to kill Treg cells in vitro using both ADCC and antibody-drug conjugates (ADC). Citation Format: Brad Screnci, Hayley Roth, Sarah Campbell, David Tucker, Colleen Fenn-Ulke, Erin Rosenberg, Meghan Pitts, Naomi Saint-Jean, Jawhara Karam, Paige Murphy, Daniela Reyes, Janae Latta, Kyle Guldner, Samantha Gilman, Tim Phillips, L. Joe Stafford, Breanna Tyrell, Kristen Shema, Chidananda Sulli, Nick Molino, Allison Snyder, Marianne Assogba, Janvi Shah, McKayla Zimmerman, Trevor Barnes, Riley Payne, Alyssa Cunningham, Elisabeth Charrier, Holden Ohl, Kyle Doolan, Ileine Sanchez, Joseph B. Rucker, Ross Chambers, Benjamin Doranz. Discovery of CCR8 antibodies targeting regulatory T cells to enable tumor sensitization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1543.