Development of Antibody-Drug Conjugates Targeting L1CAM to Treat Metastatic Cancer

Area of Science:

• Oncology
• Immunology
• Drug Development

Background:

• Metastatic cancer relapse is driven by drug-resistant metastasis stem cells (MetSCs).
• L1 cell adhesion molecule (L1CAM) is a surface marker selectively expressed on MetSCs.
• Previous L1CAM-targeting strategies have not achieved clinical success.

Purpose of the Study:

• To develop novel antibody-drug conjugates (ADCs) targeting L1CAM for the elimination of MetSCs.
• To evaluate the efficacy and safety of L1CAM-targeting ADCs in preclinical models of advanced solid tumors.

Main Methods:

• Generation of high-affinity, specific monoclonal antibodies (mAbs) against the L1CAM extracellular domain.
• Conjugation of L1CAM-targeting mAbs to the cytotoxic payload PNU-159682 to create ADCs with cleavable and non-cleavable linkers.
• Assessment of ADC-mediated cell killing in vitro and tumor control/survival in vivo in xenograft and metastasis models.

Main Results:

• L1CAM ADCs potently killed L1CAM-expressing cancer cells in vitro.
• Monotherapy with L1CAM ADCs achieved robust tumor control and extended survival in mice with L1CAM+ xenografts and lung metastases.
• Safety analyses suggest a feasible therapeutic window for L1CAM ADCs.

Conclusions:

• L1CAM ADCs represent a promising therapeutic strategy for treating advanced solid tumors.
• These novel ADCs demonstrate strong preclinical proof-of-concept for targeting L1CAM+ metastasis stem cells.
• Further preclinical development of L1CAM ADCs is warranted for clinical application.