Journal: Clinical cancer research : an official journal of the American Association for Cancer Research
This study reports the preclinical and early clinical characterization of three next-generation anti–CTLA-4 antibodies designed to enhance antitumor efficacy while reducing peripheral immune toxicity:
1. Antibody formats studied
- • Peptide-masked (PROBODY, PB): Conditionally activatable anti–CTLA-4 designed to be inactive in the periphery and activated in the tumor microenvironment.
- • Nonfucosylated (NF): Engineered Fc region to enhance effector function and T-cell priming.
- • Combined NF-PB (BMS-986288): A nonfucosylated, peptide-masked antibody integrating both design elements.
2. Methods
- • In vitro assays: Functional assays to assess T-cell priming and CTLA-4 binding/activity.
- • In vivo mouse models: Evaluation in mouse models of colorectal cancer and non–small cell lung cancer for antitumor activity, immune effects, and survival.
- • Peripheral immune responses: Assessment in non-human primates and in patients with solid tumors.
3. Key findings
- • NF antibody
- – Showed greater T-cell priming and superior antitumor activity compared with both ipilimumab and the unmasked PB antibody in cell-based systems and mouse models.
- • PB antibody
- – Intact (masked) PB showed minimal CTLA-4 binding and little peripheral immune activation.
- – Upon unmasking, functional activity was restored to levels comparable to ipilimumab.
- • NF-PB (BMS-986288)
- – Once unmasked, retained the enhanced functional potency of the NF antibody.
- – Demonstrated more pronounced antitumor activity, stronger effector memory T-cell responses, and longer survival in mouse models than ipilimumab.
- – Showed reduced peripheral immune activation compared with NF and ipilimumab in non-human primates and in patients with solid tumors.
4. Conclusion
The NF-PB anti–CTLA-4 format (BMS-986288) combines enhanced antitumor activity and immune memory with decreased peripheral immune activation in preclinical and early human data, supporting its potential as a safer, more effective CTLA-4–targeted therapy for solid tumors.