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1342 A novel dual CAB Nectin-4 x CD3 bispecific antibody targeting solid tumors
  1. Ana Paula G Cugnetti,
  2. Mathew Lucas,
  3. Haizhen Liu,
  4. Charles Xing,
  5. Jing Wang,
  6. Patty McNeely,
  7. Solimarie Joyner,
  8. Kyrie Johnson,
  9. Kathryn Woodard,
  10. Wei Zhou,
  11. Cathy Chang,
  12. Gerhard Frey,
  13. William J Boyle and
  14. Jay M Short
  1. BiAtla Inc., San Diego, CA, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Nectin-4 is a Ca2+ independent immunoglobulin-like protein that is primarily involved in cell-cell adhesion. Nectin-4 is overexpressed in several tumor types, including breast, lung, urothelial, colorectal, pancreatic, and ovarian cancers. Overexpression of Nectin-4 is associated with multiple aspects of tumor progression such as proliferation, angiogenesis, epithelial to mesenchymal transition, metastasis, DNA repair and tumor relapse. This overexpression is correlated with poor prognosis, making Nectin-4 an attractive target for developing new therapeutic strategies for cancer. As a result, a substantial number of antibody drug conjugates targeting Nectin-4 are under development. Most of these therapies, however, display a high rate of drug related toxicities accentuating the need for alternative approaches for anti-cancer therapeutics targeting Nectin-4.

Methods We leveraged BioAtla’s Conditionally Active Biologic (CAB) platform to develop a dual CAB T cell engager (TCE) bispecific antibody targeting Nectin-4 and CD3 receptors (CAB-Nectin-4 x CAB-CD3 bispecific antibody). The dual CAB Nectin-4 x CD3 bispecific antibody was engineered to bind with high affinity to both Nectin-4 and CD3 receptor antigens under conditions that mimic the acidic tumor microenvironment, but with lower binding activity in physiological (alkaline) conditions.

Results Our data demonstrate that the dual-CAB bispecific antibody promotes cytotoxicity of Nectin-4-expressing cancer cells in vitro and induces complete tumor regression in vivo. Further, the dual CAB Nectin-4 x CD3 bispecific antibody has higher potency in inducing primary T cell activation measured by means of cytokine release and cancer cell cytotoxicity under acidic conditions compared to the non-CAB benchmark bispecific antibody. In non-human primates, a single dose of the dual-CAB bispecific antibody was well-tolerated at a dose of 5 mg/kg. Non-CAB Nectin4 x CD3 bispecific antibody was also well tolerated at a dose of 5mg/kg but induced high levels of IL-6, while the CAB Nectin-4 x CAB CD3 bispecific antibody induced minimal IL-6 cytokine response.

Conclusions The generation of CAB T-cell engagers (TCEs) with activity in the disease microenvironment minimizes on-target, off-tumor toxicities, thereby enabling TCEs with strong anti-tumor activity and increased tolerability for potentially enhanced therapeutic index in the clinic.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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