Advancing Development of Novel Immunotherapy for Chemotherapy-induced Peripheral Neuropathy (CIPN)

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The opioid crisis has emphasized the need for better non-addictive therapeutics for pain management. The chemotherapy-induced peripheral neuropathy (CIPN) imposed on approximately half of patients receiving oxaliplatin treatment for cancer is a significant additional burden. While sophisticated molecular tools are now being introduced to attack cancer and despite severe adverse effects, oxaliplatin chemotherapy remains in wide usage as a primary treatment response at many sites. Its high prevalence of neurotoxicity often limits chemotherapeutic dosing efficacy and maximum therapeutic effect. Patients can experience disabling cold and mechanical hypersensitivity that persist for years after treatment. The toxic effects can cause premature termination of treatment, impacting quality of life and survivability. CIPN can lead to permanent symptoms and disability in up to 40% of cancer survivors subsequently, thus the societal loss in dollars is inestimable. There are no drugs preventing development of CIPN, and CIPN has a poor therapeutic response to analgesics. Our current collaborative effort focuses on optimizing a small molecule single chain Fragment variable antibody (scFv) therapy that reverses chronic neuropathic pain. Smaller engineered scFvs (25-28 kDa) feature similar binding activity but stronger tissue and brain penetrability. These small molecules are considered suitable drug candidates for pain control since they satisfy key parameters such as (1) high affinity for the therapeutic target, (2) high thermostability, (3) lack of aggregation, and (4) availability from high expression cell lines. Commercial viability is dependent on humanization and affinity purification of the current patent pending small brain penetrant scFv therapy effective in murine models. The objective of this proposal is to humanize the current small scFv antibody and while maintaining more than 50% effectiveness in the murine CIPN pain model. The methodology used will be to ascertain the minimum requirements for humanization, affinity maturation, and then to bench test the antibody for effectiveness in the CIPN model vivo and in in vitro models including human-like neurons, expression systems, and primary sensory neurons from CIPN mice to validate feasibility for continuing with human clinical trials. Finally, we will seek independent commercial confirmation to demonstrate safety with PK/PD, distribution, and toxicology validation studies. The ultimate objective of this project is realization of an effective and commercially viable non-opioid treatment for chemotherapy induced neuropathic pain (CINP). The single chain Fragment variable (scFv) antibody therapy designed would prevent CINP and/or mitigate long standing, disabling CINP.