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Regular and Young Investigator Award Abstracts
Novel Single-Agent Immunotherapies
1343 Novel conditionally active bispecific HER2 x CD3 T cell engager targeting solid tumors
  1. Ana Paula G Cugnetti,
  2. Haizhen Liu,
  3. Patricia McNeeley,
  4. Mathew Lucas,
  5. Charles Xing,
  6. Solimarie Joyner,
  7. Kyrie Johnson,
  8. Kathryn Woodard,
  9. Wei Zhou,
  10. Cathy Chang,
  11. Gerhard Frey,
  12. William J Boyle and
  13. 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.

Abstract

Background Human epidermal growth factor receptor 2 (HER2) is overexpressed in multiple cancers and is associated with poor prognosis. Despite the outstanding improvement in survival with the introduction of anti-HER2 therapies, therapeutic benefit is limited by many resistance mechanisms and toxicities. Clinical trials of therapeutics redirecting T cell activity to HER2+ tumors have highlighted the apparent risk of on-target, off-tumor adverse effects for this target, as HER2 is also expressed in normal epithelia.

Methods Using BioAtla’s Conditionally Active Biologic (CAB) platform, we have developed a HER2 x CAB-CD3 bispecific antibody that was engineered to bind with high affinity to the CD3 receptor and induce T cell activation under conditions that mimic the tumor microenvironment, but with reduced binding in physiological conditions. Both in vitro and in vivo efficacy data for a CAB T cell engager (TCE) targeting HER2 will be presented.

Results Our data demonstrate that HER2 x CAB-CD3 bispecific antibody promotes cytotoxicity of HER2+ cancer cells in vitro and induces complete regression of tumor growth in vivo. The HER2 x CAB-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, the HER2 x CAB-CD3 and a non-CAB HER2 x CD3 were well-tolerated at a dose of 0.1 mg/kg. The non-CAB HER2 x CD3 bispecific antibody induced high levels of cytokines, whereas the HER2 x CAB-CD3 bispecific antibody induced only mild cytokine response.

Conclusions The generation of CAB bispecific antibodies with activity in the disease microenvironment minimizes on-target, off-tumor toxicities, thereby enabling higher potency-TCEs for targeting drug resistant, low expressing-HER2+ tumors. In summary, the use of CAB technology expands the universe of targets for drug development by generating a new class of potent CAB T-cell engagers with increased tolerability for potentially enhanced therapeutic index in the clinic.

http://creativecommons.org/licenses/by-nc/4.0/

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 http://creativecommons.org/licenses/by-nc/4.0/.

http://dx.doi.org/10.1136/jitc-2023-SITC2023.1343

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