ABBV-011, A Novel, Calicheamicin-Based Antibody-Drug Conjugate, Targets SEZ6 to Eradicate Small Cell Lung Cancer
Wolf R Wiedemeyer1, Julia Gavrilyuk1, Alexander Schammel1
1AbbVie Inc., North Chicago, Illinois.
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).
Insights
A new antibody-drug conjugate (ADC), ABBV-011, targets SEZ6 for small cell lung cancer (SCLC) treatment. This novel calicheamicin-based ADC shows potent tumor regression in preclinical studies, offering a potential new therapy for SCLC patients.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Four antibody-drug conjugates (ADCs) were approved in the past year, doubling the number of marketed ADCs in oncology.
- Successful ADCs require optimization of targeting antibody, conjugation chemistry, and payload mechanism of action.
Purpose of the Study:
- To describe the development of ABBV-011, a novel SEZ6-targeted, calicheamicin-based ADC for small cell lung cancer (SCLC) treatment.
- To identify SCLC as a tumor type with enhanced sensitivity to calicheamicin ADCs.
Main Methods:
- Engineered a calicheamicin conjugate lacking an acid-labile hydrazine linker.
- Screened a patient-derived xenograft library to identify SCLC sensitivity.
- Used RNA sequencing (RNA-seq) and immunohistochemistry (IHC) to identify SEZ6 as a surface target.
- Developed an anti-SEZ6 antibody and conjugated it to the calicheamicin payload.
Main Results:
- Identified SCLC as a tumor type with enhanced sensitivity to calicheamicin ADCs.
- Identified seizure-related homolog 6 (SEZ6) as a surface target with broad SCLC expression and minimal normal tissue expression.
- Developed an antibody targeting SEZ6 that is rapidly internalized upon binding.
- The conjugated ADC demonstrated potent tumor regression in vitro and in vivo.
Conclusions:
- ABBV-011, a novel SEZ6-targeted, calicheamicin-based ADC, demonstrates potent preclinical efficacy against SCLC.
- These data support ABBV-011 as a potential novel treatment for SCLC patients.
- Ongoing phase I studies (NCT03639194) will further evaluate ABBV-011 in patients.
