Anti-MUC16 humanized antibody combination regimen for targeting metastasis in pancreatic cancer

Abstract public domain (NIH RePORTER)

ABSTRACT This SBIR Fast-Track proposal aims to establish the efficacy of a novel therapeutic humanized antibody regimen targeting MUC16 in combination with standard-of-care chemotherapy against metastatic pancreatic ductal adenocarcinoma (PDAC) in preclinical models. PDAC is one of the most lethal malignancies characterized by early metastasis and poor response to existing therapeutic modalities. Despite the significant success achieved with monoclonal antibody (mAb) based therapies in different cancers, progress in treating PDAC remains slow due to the lack of appropriate and disease-specific targets and inappropriate model systems for testing therapeutic drugs. MUC16, a transmembrane mucin, is differentially overexpressed in PDAC with limited expression in normal organs and undergoes cleavage that results in the generation of a surface-tethered oncogenic carboxy-terminal (MUC16-Cter) domain. MUC16 and MUC16-Cter expression is strongly linked with metastasis in PDAC patients, thus rationalizing its utility for targeting. We have developed novel tools and models for understanding and targeting the pathological implications of MUC16, including a panel of antibodies targeting the oncogenic MUC16-Cter domain. One mAb, mAb5E6, is directed towards the post-cleavage generated surface-retained MUC16-Cter domain and recognizes MUC16 in advanced disease and metastatic PDAC tumors. Our preliminary data indicates that treatment with chimeric mAb5E6 decreased the proliferation and migration of MUC16-expressing PDAC cells and patient organoids and reduced tumor burden and metastasis in orthotopic pancreatic xenograft mouse models. Delineating the mechanism of action revealed that mAb5E6 abrogated signaling associated with MUC16-mediated EMT, a feature associated with metastasis in PDAC. We hypothesize that the humanized mAb5E6 will specifically target MUC16-associated metastasis in PDAC. During Phase 1, Aim 1 will characterize the production of therapeutic-grade humanized mAb5E6 and its biophysical and biochemical characterization. Aim 2 will assess the efficacy of humanized mAb plus standard-of-care chemotherapeutic regimen for its anti-proliferative and anti-metastatic effects on MUC16-expressing PDAC cell lines and tumor xenografts in nude mice. In Phase II, Aim 1 will test the efficacy of a humanized mAb5E6 and combination regimen in MUC16-stratified PDAC patient-derived organoids, ex vivo metastatic organoids, and preclinical mouse models of metastasis. Aim 2 will determine the efficacy and safety of antibody combination regimens in immune intact humanized Hu-SCID and FcRn mouse models for IND-enabling. Based on these studies, we will contact the FDA to set up a pre-IND informational meeting and seek guidance to undertake further toxicity studies in non-human primates (NHPs). Successful completion of Phase II SBIR goals will provide the key results and data to engage private-sector investors/partners in the following steps toward the regulatory approval required to begin clinical trials.

Public health relevance public domain (NIH RePORTER)

Project Narrative The current proposal aims to establish the efficacy and safety of a novel anti-MUC16 humanized antibody combination treatment regimen in PDAC. This application is focused on targeting metastasis in PDAC by a unique antibody directed towards the clinically pertinent epitope of MUC16 and determining if a combination with standard-of-care chemotherapy can enhance durable responses. This proposal validates the anti-MUC16 mAb5E6 combination regimen for clinical development.