Immunoprofiling of Opioid Use Disorder Patients to inform structure-guided design of opioid-specific monoclonal antibodies

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ABSTRACT: Immunoprofiling of Opioid Use Disorder Patients to inform structure-guided design of opioid- specific monoclonal antibodies The opioid use disorder (OUD) and opioid-related overdoses are a national emergency. Over >100,000 overdose deaths occurred in the period between April 2020 and April 2021, which are largely driven by fentanyl alone or mixed with other opioids or psychostimulants. Since the initiation of the COVID-19 pandemic, there has been an increase in non-fatal overdoses requiring hospitalization. These statistics clearly indicate that approved pharmacotherapies are not sufficient in preventing or treating OUD and opioid overdose. Antigen- specific monoclonal antibodies (mAbs) are isolated from the antigen, or by vaccine-induced polyclonal antibody response. Compared to conventional treatment methods based upon small molecule-based pharmacotherapies targeting the brain mu opioid receptor (MOR), mAbs bind and form a complex with the drug molecule in circulation. Hence, administration of mAbs impedes drugs from crossing blood-brain-barrier through sequestration of the molecules, blunting their CNS effects. Compared to MOR-ligands, mAb offer longer lasting efficacy and no interference with off-target drugs. Therefore, the proposing study focuses on: 1) functional characterization of the human opioid-specific B cell receptor (BCR) repertoire paired with isolation of opioid-specific mAb; 2) structure-guided design of humanized and human mAbs with greater efficacy and selectivity. The research approach will involve complementary strategies to identify potential mAb candidates including next-generation sequencing based-BCR sequencing, antibody display and antibody engineering, to validate the hypothesis that pairing OUD- or vaccine-induced BCR genetic variability with structure-guided antibody design will identify mAb with greater therapeutic potential. Moreover, the proposed study will inform us of how OUD and vaccination introduces antigen-specific genetic perturbations in BCRs. With knowledge of antibody structure, the result of this study will lead to generation of mAbs with improved affinity. To achieve these goals, AIM 1 delineates the evolution of human BCR repertoire in OUD patients who are immunized with a conjugated oxycodone-specific vaccine in Phase I clinical trials (NCT04458545) and unimmunized OUD patients. AIM 2 tests the relevance of the opioid-specific Fab structure to the mAb efficacy and selectivity. The results of the study will expand our understanding on the human opioid-specific antibody and B cell repertoire, supporting structural-based antibody engineering to generate mAbs with high affinity. Moreover, the results can accelerate the development of antibody-based strategy as an alternative and complementary solution treating opioid overdose.