Harnessing TNB-486: A Fully Human Bispecific Antibody for Targeted Elimination of CD19-Positive Tumors with Reduced Cytokine Release

CD19 is a potential target for treating B-cell cancers due to its limited expression in this lineage. Various therapies targeting CD19, such as monoclonal antibodies and antibody drug conjugates, have been developed. Innovative approaches like bispecific T-cell redirecting antibodies (T-BsAbs) and anti-CD19 chimeric antigen receptor T-cells (CAR-T) have shown promise, particularly in treating leukemia and lymphoma. However, the risk of toxicity, particularly neurotoxicity, due to excessive T-cell activation remains a significant challenge.

TNB-486, a newly designed CD19 x CD3 T-BsAb, aims to address this issue by maintaining anti-tumor activity while minimizing the cytokine secretion associated with toxicity. The development of TNB-486 utilized TeneoSeek, a next-generation sequencing (NGS) platform that enhances the discovery of antigen-specific antibodies. This process resulted in the creation of a high-affinity αCD19 HCA and a diverse αCD3 Flic antibody library, which included a low-activating αCD3 variant that triggered minimal cytokine release without compromising T-cell dependent lysis of lymphoma cells.

In vitro and in vivo studies were conducted to evaluate TNB-486's efficacy and therapeutic potential. Affinity and stability assessments were performed using Biacore and flow cytometry, respectively. T-cell activation and cytokine levels were measured using flow cytometry and ELISA methods. In vivo studies involved NOG mice implanted with CD19-positive tumor cells and treated with TNB-486, with tumor growth and response monitored.

Results indicated that TNB-486 demonstrated high affinity for CD19 and comparable cytotoxicity to strongly activating bispecific antibodies at lower doses. Importantly, it induced significantly less cytokine release, suggesting a reduced risk of toxicity. In vivo, TNB-486 effectively eliminated all tested CD19-positive tumors at minimal doses and showed a pharmacokinetic profile similar to other IgG molecules.

In conclusion, TNB-486 shows potential as a differentiated lymphoma therapy, offering comparable tumor cell lysis with reduced cytokine secretion. The absence of off-target effects and its efficacy in established tumor models highlight its promise as a novel therapeutic option.

The disclosures section lists affiliations and interests of the authors, all of whom are associated with Teneobio, Inc., indicating potential conflicts of interest related to employment and equity ownership.