Rational Design of Immuno-Oncology Biologics with Improved Safety and Efficacy
Kurt Jenkins1, Miso Park1, Parker Johnson1, Asaul Gonzalez1, Veronica Flesch1, Tim Miles1, Ulrich Rodeck2, John Williams1, Margaret Karow3
1City of Hope, 2 Thomas Jefferson University, 3 Akriveia Therapeutics Inc.
The benefit of enhancing anti-tumor immune response has been demonstrated by the unprecedented clinical responses to immune checkpoint antagonists and cell-based therapies. Yet, systemic activation of the immune system by these agents frequently leads to immune related adverse events (irAEs), which can be severe. Restricting the activity of immuno-oncology agents to the tumor microenvironment is expected to overcome the limitations on dosing and efficacy posed by irAEs. We have developed a rational approach (termed Aklusion™) to efficiently design immuno-therapeutics that are locally activated in the tumor microenvironment and exhibit reduced systemic activities. Activation relies on the proteolytically active tumor micro environment.
We used anti-mouse CTLA4 antibody 9D9 and anti-mouse PD1 antibody J43 to demonstrate the benefits of localizing pharmacological activity of immuno-oncology agents to the tumor microenvironment. In vitro testing of antigen binding by Surface Plasmon Resonance (SPR), antigen-capture ELISA and kinetic assays provided important information to guide and support the design process. This data showed that Akluded, tumor-activatable antibodies exhibited significantly reduced affinity for their targets prior to activation, and full binding affinity was restored after proteolytic activation. In vivo testing of both Akluded antibodies demonstrated growth inhibition of syngeneic MC38 transplants similar to the corresponding parental antibodies. In vivo tumor growth inhibition was dependent on protease activity. Critically, the Akluded antibodies exhibit reduced levels of systemic activity compared to their parental antibody. Collectively, these data indicate the potential of Aklusion to improve the therapeutic index of antibodies, and biologics in general, to enable higher and longer dosing of immuno-therapeutics as single agents and in the most potent combinations.
1. Donaldson JM, Kari C, Fragoso RC, Rodeck U, and Williams JC: Design and development of masked therapeutic antibodies to limit off-target effects: Application to anti-EGFR antibodies: Cancer Biology & Therapy (2009) 8:22; 2145-2150