LY4152199, a First-in-Class BAFF-RxCD3 Bispecific Antibody for the Treatment of B Cell Malignancies

The treatment paradigm for B-cell malignancies has been evolving with the availability of newer therapies such as CD19 CAR-Ts, as well as CD19×CD3 and CD20×CD3 bispecific antibodies. However, CD19/20 antigen loss can affect the long-term response to these treatments, which occurs frequently in patients who relapse following CD19/CD20-targeted therapy. BAFF-R (also known as TNFRSF13C or BR3) is a TNF-receptor super-family member that is essential to B-cell development and survival. Less broadly expressed than CD19 and similar with CD20, BAFF-R is expressed as a surface protein by most of B cells, including both healthy and malignant B cells, starting from late pre-B lymphocytes and ending before terminally differentiated plasmablasts and plasma cells. Importantly, BAFF-R expression appears unaffected after CD19/20 antigen loss. We have developed a fully human BAFF-R×CD3 bispecific antibody using a common light chain on an effector-less IgG1 backbone, LY4152199, that engages BAFF-R on the surface of B cells and CD3 on the surface of T cells, which leads to effective T cell-mediated elimination of BAFF-R-expressing malignant B cells. LY4152199 binds BAFF-R with high affinity. In co-culture assays with T cells and BAFF-R-expressing malignant B cells, LY4152199 engaged both CD3 and BAFF-R to induce concentration-dependent T-cell activation and T-cell mediated cytotoxicity, which was more potent than mosunetuzumab, a comparator CD20xCD3 bispecific antibody and a clinical benchmark for a TCE with lower cytokine release syndrome in B cell malignancies. Furthermore, LY4152199-induced in vitro cytokine production was lower than that observed for mosunetuzumab. In human PBMC transplanted mouse models implanted with human B cell lymphomas expressing physiologically relevant levels of BAFF-R, weekly treatment with LY4152199 demonstrated robust anti-tumor activities, including tumor clearance in 2 models. In addition, LY4152199 resulted in comparable or lower levels of human cytokines in the serum from these animals compared to animals treated with mosunetuzumab. Lastly, LY4152199 showed IgG-like pharmacokinetics and low immunogenicity. Taken together, LY4152199 exhibits specificity, desirable functional activity and good developability. It has demonstrated the potential as a first-in-class BAFF-RxCD3 bispecific antibody to treat BAFF-R-positive B cell malignancies, including relapsed or refractory cases with CD19/CD20 expression loss.