GIGA-564, a Third-Generation Anti-CTLA-4, Has Enhanced Efficacy But Reduced Toxicity Compared To IPILIMUMAB in PRE-CLINICAL MODELS .
Checkpoint Inhibitors .
Anti-CTLA-4 Antibodies Such as IPILIMUMAB Were Among The First Immune-Oncology Agents To Show Significantly Improved Outcomes For Patients .
However, existing anti-CTLA-4 Therapies Fail to induce a Response in a Majority of Patients and can Induce Severe, Immune-Related Adverse Events .
It Has Neen Assumed that Checkpoint inhibition, i.e., Blocking The Interaction Between CTLA-4 and Its Ligands, is The Primary Mechanism of Action For IPILIMUMAB .
Here We Present Evidence that Checkpoint Inhibition May Not be The Primary Mechanism of Action for Efficacy of Anti-CTLA-4 Antibodies .
Instead, a Primary mechanism For Efficacy is FcR-mediated Treg Depletion in the Tumor MicroEnvironment .
We identified a Monoclonal Antibody (mAb), GIGA-564, that binds to CTLA-4 at an epitope that differs from IPILIMUMAB’s by only a few amino acids, yet has limited Checkpoint Inhibitor Activity .
GIGA-564 Also Induces less Treg Proliferation and has Increased Ability to Inducein VitroFcR Signaling Andin VivoDepletion of Intratumoral Tregs .
Further experiments Showed that the Enhanced FcR Activity of GIGA-564 likely contributes to its Enhanced ANTI-TUMOR Activity .
Importantly, We Also Showed That GIGA-564 Was Associated With Lower Toxicity in Murine Models .
Our Work Suggests That New Anti-CTLA-4 Drugs Should be Optimized For Treg Depresión Rather Than Checkpoint Inhibition .
Erica Stone,Vice President, Oncology,GigaGen Inc .
Last Published : 13/Jan/23 .