R21: A novel antibody-drug conjugate for treatment of squamous cell lung carcinoma

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A novel antibody-drug conjugate for treatment of squamous cell lung carcinoma Project Summary With few available treatments, lung squamous cell carcinoma (SCC) has a 5-year survival of only 21%. This proposal outlines a novel antibody-drug conjugate (ADC) therapy for lung SCC, which targets and delivers a highly potent chemotherapy monomethyl auristatin E (MMAE) to G protein-coupled receptor 87 (GPR87)- overexpressing SCC tumors. ADCs combine the advantages of the high specificity of a targeting antibody and the high potency of a cytotoxic drug, and therefore, have the potential to improve the efficacy of the drug and reduce off-target toxicity. We will employ a new reliable approach for drug conjugation that utilizes supramolecular assembly of coiled coil peptides. This method allows site-specific, uniform loading of two drug molecules at the Fc region per antibody and maintains targeting specificity of the Fab region. The strong binding affinity of the coiled coils enhances ADC stability and prevents premature release of the drug. Moreover, the approach allows facile pairing of antibodies and drugs under mild aqueous conditions. The proposed experiments will test the hypothesis that an αGPR87 antibody-MMAE conjugate will target lung tumors, reduce systemic toxicity of MMAE, and extend survival, compared to a conventional ADC and MMAE alone in a SCC patient-derived xenograft (PDX) model. Importantly, well-characterized materials and rigorous experimental designs are established in this proposal with essential cross-disciplinary collaborations and expertise. The aims of this exploratory and developmental proposal are as follow. Aim 1 determines immunogenicity of the ADC components, and plasma stability, tumor binding and cytotoxicity of the ADC in human lung cancer and normal cell lines. Aim 2 evaluates biodistribution, PK, systemic toxicity and efficacy of the ADC in a SCC PDX model. Successful development of this ADC delivery platform will generate a novel targeted therapy with minimal off-target toxicity for SCC. Our supramolecular self-assembly conjugation approach also provides a versatile conjugation strategy applicable to other antibody-drug pairs for treatment of other cancers and diseases.