Pre-Clinical Evaluation of AZD5492, a Novel CD8-Guided T Cell Engager, for B-Non Hodgkin Lymphoma Indications

Introduction Non-Hodgkin lymphomas (NHL) include diverse neoplasms of the lymphoid compartment, with the majority originating from the B-cell lineage. Bispecific CD20xCD3 T cell engagers (TCEs), both monovalent and bivalent, have shown promising rates of ORRs and CRs in the clinic leading to several FDA approvals for the treatment of R/R DLBCL and FL. However, these treatments are still associated with significant toxicities, including CRS and ICANS, limiting their therapeutic window and potential for clinical combinations. Methods We engineered a first-in-class CD8-guided TCE, AZD5492, for B-NHL malignancies. AZD5492 is an asymmetric, trispecific monoclonal IgG1 antibody which harbors two Fab binding domains to CD20, one VHH binding domain to TCR, one VHH binding domain to CD8 co-receptor. AZD5492 binding, cytolytic activity, and efficacy were extensively interrogated in vitro and in vivo, in murine models and in non-human primates (NHP). Results The VHH domains of AZD5492 allow preferential engagement of CD8+ T cells through CD8/TCR binding, leading to the formation of an artificial immunological synapse with CD20+ target cells, T-cell activation and target B cell killing. Compared to conventional CD20xCD3 TCEs, which equally engage and activate CD4+ and CD8+ T cells, AZD5492 drives potent B cell killing through preferential engagement of CD8+ T cells, with reduced CD4+ T cell activation and associated cytokine production. In NSG humanized mice engrafted subcutaneously or intravenously with B cell tumors, AZD5492 conferred potent and dose-dependent anti-tumor efficacy. When compared to conventional bivalent CD20xCD3 TCEs, comparable anti-tumor efficacy was achieved with significantly less systemic cytokine production. Importantly, repeated dosing of AZD5492 was also evaluated in cynomolgus monkey for up to 1 month and induced a marked and prolonged decrease in CD19+ and CD20+ B cells in the blood and in tissues (lymph nodes, spleen, and bone marrow). Transient cytokine increases were observed post-first dose of AZD5492 but was not associated with notable toxicity. Overall, AZD5492 was well tolerated in cynomolgus monkeys and a NOAEL was established at 3 mg/kg. Conclusions AZD5492 represents a first-in-class T cell engager for the treatment of B cell lymphomas. Compared to conventional CD3-based T cell engagers, AZD5492 anti-tumor activity in murine models was associated with low cytokine release and this favorable safety profile was recapitulated in NHP. AZD5492 has therefore the potential to significantly improve therapeutic index. AZD5492 IND has been approved by the FDA and a FIH study in patients with R/R NHL and CLL is ongoing.