Lead identification of therapeutic anti-glycan antibodies for cancer therapy

Siamab Therapeutics, Inc., Newton MA

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Abstract

DESCRIPTION (provided by applicant): The capacity to distinguish normal from malignant cells in a consistent and reliable fashion remains an important but often elusive goal for cancer therapy. Aberrant forms of glycosylation been described in numerous human cancers, identifying glycans as an entirely novel class of tumor-associated antigens suitable for specific tumor targeting. While the presence of the sialylated version of the Tn antigen (STn) in normal adult human tissues is extremely rare, STn occurs frequently in various human cancers, and can thus be considered to be a tumor-associated antigen. The presence of STn in tumors is associated with poor prognosis and reduced overall survival; therefore, STn is considered an attractive target for cancer therapy. STn as a target for cancer therapy has been studied in both preclinical and clinical settings to date solely using vaccines. The most advanced clinical candidate was Theratope, which consists of synthetic STn coupled to a KLH carrier. While in mouse studies Theratope immunization induced a potent antibody response that was shown to delay growth of STn-expressing mammary carcinoma cells, the vaccine failed to meet its primary endpoint in a phase III non-stratified clinical trial, although a post-hoc analysis reveale activity in a subset of patients. Importantly however, these investigations have demonstrated the safety and potential therapeutic benefit of targeting STn. To our knowledge no considered effort has been expended to develop other types of therapeutic agents beyond vaccines, such as monoclonal antibodies (mAbs) that target STn and also can be used as companion diagnostics. Sialix is committed to meet this unmet need and has already created a panel of anti-STn mAbs that possess high binding affinity and exquisite specificity toward the STn target in a protein-independent fashion. Importantly, Sialix has recently demonstrated that one of its mAbs is capable of significantly reducing tumor growth in an in vivo orthotopic syngeneic model of murine breast cancer where, strikingly, tumor regression was also observed. During the requested SBIR Phase I funding period Sialix will extend and expand these initial extremely promising studies by performing in vitro assays to i) assess the antibody-dependent cellular cytotoxicity (ADCC) activity of each of the 7 anti-STn antibodies in the panel; ii) evaluate the capacity of the mAbs to be internalized into human tumor cells, revealing the potential for future payload conjugation; and iii) determining their cancer specificity using tissue microarrays. Lastly from analysis of the generated in vitro data, a subset of mAbs will be examined for their anti-tumor activity in an orthotopic model of human breast cancer. The end goal of the Phase I study will be to choose 1-2 mAbs for humanization and additional activities that will comprise a Phase II program toward eventual filing of an IND.