Targeting Cd46 to Enhance Therapeutic Outcomes – A New Checkpoint Inhibitor Technology Directed at the Complement System
Jiho Kim1,2, Sean Gray2, Andre Lieber3, Darrick Carter1,2,3
1Department of Global Health, University of Washington, Seattle, WA
2PAI Life Sciences, Seattle, WA
3Department of Medical Genetics, School of Medicine, University of Washington, Seattle, WA
We have engineered a recombinant adenoviral knob protein to bind with high avidity to CD46 (also known as membrane cofactor protein, MCP), a complement inhibitor. The therapeutic, AD35K++, is a recombinant protein derived from adenovirus subtype 35 which enters the cell by binding CD46 on the surface of the cell. AD35K++ has nanomolar affinity to CD46 (Kd = 0.63 nM) and is able to mediate internalization and degradation of CD46 from the cell surface. CD46 has been previously found to be overexpressed on multiple types of tumors, ostensibly to avoid the complement-mediated cytotoxic response. In vivo and in vitro studies have shown that AD35K++ in combination with commercially available monoclonal antibodies drastically improves tumor cell killing and treatment outcomes. In addition, low immunogenicity and toxicity of the protein therapeutic in non-human primates make AD35K++ a promising candidate for clinical trials of combination therapy.
As the complement cascade mediates numerous processes throughout the immune system, we have also investigated other effects that AD35K++ and its inhibition of CD46 may have. Stimulation of naïve T-cells with AD35K++ seems to shift the phenotype towards a more inflammatory Th1-like phenotype. We are now focusing on new uses of the protein and identifying the gene expression signatures and pathways which are responsible for these phenotypes. In this presentation, we will report on translational activities in anticipation of human clinical trials. We present our data about the properties and efficacy of AD35K++ in cancers, and potential uses and directions for the protein in other fields.
This research was supported by the National Heart, Lung and Blood Institute (R43-HL131195), and the National Cancer Institute (R43-CA183379, R21-CA193007).