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Background Human leukocyte antigen G (HLA-G), a non-classical MHC class I molecule expressed on solid tumors, is known to drive immune suppression, promote cancer cell immune escape and lead to tumor development and growth. HLA-G mediates suppression through ILT2 and ILT4 on adaptive (ILT2) and innate (ILT2 & ILT4) immune cell subpopulations. Blocking HLA-G has the potential to reverse immune tolerance and activate anti-tumor immune responses.Methods and Results TTX-080 is a novel, first-in-class, fully human monoclonal antagonistic antibody that is designed to specifically bind to HLA-G and block interactions with both ILT2 and ILT4. TTX-080 is currently in Phase 1 clinical development as a monotherapy and in combination with pembrolizumab, cetuximab (anti-EGFR IgG1:FcgR ADCC & ADCP competent), and FOLFIRI + cetuximab in patients with metastatic or advanced cancer.Here we present translational data demonstrating the significant TTX-080 on-mechanism activation of innate and adaptive immune cells in the tumor microenvironment and in the periphery validating the functional impact of HLA-G blockade on immune cells in a clinical setting.As a monotherapy, increased activation of myeloid genes (phagocytosis & ADCP) was observed comparing tumor samples pre- vs post-treatment. When evaluating peripheral changes, increased frequency of activated innate KI67+ NK cells (cytotoxicity & ADCC activity) was detected via flow cytometry. In addition, increased numbers of activated antigen experienced ILT2+CD8+ T cells (TEMRA), and CD4+ T cells were found highlighting changes to the adaptive immune response and differentiation of the HLA-G/ILT2/ILT4 pathway from conventional checkpoint therapies like anti-PD-(L)1, where exhausted T cells are predominately impacted. Further, serum levels of the chemo-attractants CXCL9 & CXCL10, known to be associated with tumor associated macrophages and recruitment of effector T cells were elevated.An additional observation from peripheral ctDNA analysis showed that patients who achieved clinical benefit from the combination of TTX-080 + cetuximab (PR = partial response, CR = complete response, or SD = stable disease > 90 days) had low tumor mutational burden (TMBlow status), a population that has been resistant to traditional immunotherapy approaches to date.Conclusions Taken together, TTX-080 offers a differentiated mechanism-of-action that has the potential to activate both the innate and adaptive immune response and combination rationale with ADCC and ADCP competent therapeutics.