Harnessing Tumor-Infiltrating Lymphocytes to Produce Engineered Polyclonal Antibody Therapies

Counteracting tumor adaptation is a long-standing challenge in oncology. Targeted therapies are susceptible to escape following mutation, shedding, or downregulation of the tumor antigen. To conceptualize a strategy enabling broad tumor targeting, we turned to tumor-infiltrating B cells (TIL-B). TIL-B are linked to favorable prognosis and were demonstrated to promote response to immune checkpoint blockade.
We enrich, culture and differentiate TIL-B from patient tumors to produce the first Intravenous Immnuoglobulin (IVIg) therapy for oncology. Oncologic, Multi-epitope General (OMG) antibodies purified from TIL-B cell cultures effectively bind patient-derived tumor cells and cell lines from similar tumor types, but not healthy tissues. In comparison to plasma derived antibodies, OMG antibodies are more potent at facilitating tumor cell killing. Uniquely, employing CRISPR/Cas9 and AAV to engineer antibody-coding genes, we force secretion of T cell engager (TCE) molecules. Compared to non-engineered OMG antibodies, engineered OMG display improved anti-tumor activity while retaining polyclonal tumor specificity. Importantly, we produced engineered anti-tumor IVIg for a wide variety of solid malignancies and combining several sources of antibodies improves the breath of these therapies.
We propose that OMG antibody therapy should be considered as an innovative IVIg for oncology and as a scalable and effective strategy to counter tumor resistance.