Enhancing Cancer Immunotherapy: The CAB CTLA4 Antibody Approach to Mitigate Immune-Related Adverse Events

CTLA4, a T-cell receptor, can be targeted to enhance immune responses against cancer. However, the use of anti-CTLA4 therapies, such as ipilimumab, has been associated with significant toxicities due to systemic immune activation. The Conditionally Active Biologics (CAB) technology addresses this by developing antibodies that bind to target antigens in diseased tissues, like cancer, but not in normal tissues, capitalizing on the unique cancer microenvironment.

The CAB-CTLA4 antibodies identified through this technology have shown to selectively enhance T-cell responses in the tumor microenvironment without affecting normal tissues. In a syngeneic human CTLA4 knock-in mouse model, CAB-CTLA4 demonstrated comparable antitumor efficacy to ipilimumab, including tumor regression in a MC38 colorectal tumor model. Unlike ipilimumab, CAB-CTLA4 antibodies did not increase CD4 effector T cells in peripheral blood, suggesting a reduced risk of systemic immune toxicities.

In a study involving monkeys, the combination of ipilimumab and an anti-PD-1 analog led to increased T cell proliferation markers in peripheral blood and gastrointestinal symptoms, while CAB-CTLA4 combined with the anti-PD-1 analog maintained normal immunophenotypic patterns and showed no gastrointestinal issues. This indicates that CAB-CTLA4 may offer a superior safety profile when combined with PD-1 inhibitors, potentially allowing for increased dosing to achieve better efficacy than current anti-CTLA4 therapies, both as a single agent and in combination with other cancer treatments.