ABBV-011, A Novel, Calicheamicin-Based Antibody-Drug Conjugate, Targets SEZ6 to Eradicate Small Cell Lung Cancer Tumors.

Abstract

In the past year, four antibody-drug conjugates (ADC) were approved, nearly doubling the marketed ADCs in oncology. Among other attributes, successful ADCs optimize targeting antibody, conjugation chemistry, and payload mechanism of action. Here, we describe the development of ABBV-011, a novel SEZ6-targeted, calicheamicin-based ADC for the treatment of small cell lung cancer (SCLC). We engineered a calicheamicin conjugate that lacks the acid-labile hydrazine linker that leads to systemic release of a toxic catabolite. We then screened a patient-derived xenograft library to identify SCLC as a tumor type with enhanced sensitivity to calicheamicin ADCs. Using RNA sequencing (RNA-seq) data from primary and xenograft SCLC samples, we identified seizure-related homolog 6 (SEZ6) as a surface-expressed SCLC target with broad expression in SCLC and minimal normal tissue expression by both RNA-seq and IHC. We developed an antibody targeting SEZ6 that is rapidly internalized upon receptor binding and, when conjugated to the calicheamicin linker drug, drives potent tumor regression in vitro and in vivo. These preclinical data suggest that ABBV-011 may provide a novel treatment for patients with SCLC and a rationale for ongoing phase I studies (NCT03639194).

• Authors: Wolf R Wiedemeyer, Julia Gavrilyuk, Alexander Schammel, Xi Zhao, Hetal Sarvaiya, Marybeth Pysz, Christine Gu, Monica You, Kumiko Isse, Theodore Sullivan, Dorothy French, Christina Lee, Angeline T Dang, Zhaomei Zhang, Monette Aujay, Alexander J Bankovich, Philip Vitorino
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 21 Issue 6 Pg. 986-998 (06 01 2022) ISSN: 1538-8514 [Electronic] United States
• PMID: 35642431 (Publication Type: Journal Article)
• Copyright: ©2022 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Calicheamicins
• Immunoconjugates

Topics

• Antineoplastic Agents (pharmacology)
• Calicheamicins
• Clinical Trials, Phase I as Topic
• Humans
• Immunoconjugates (pharmacology, therapeutic use)
• Lung Neoplasms (drug therapy)
• Small Cell Lung Carcinoma (drug therapy, genetics)