3D-Informed Targeting of the Trop-2 Signal-Activation Site Drives Selective Cancer Vulnerability

Area of Science:

• Oncology
• Immunology
• Biochemistry

Background:

• Trop-2 targeted therapy for advanced cancers is limited by Trop-2 expression in normal tissues.
• Trop-2 is proteolytically activated by ADAM10 in cancer cells, exposing a unique binding groove.

Purpose of the Study:

• To develop a novel Trop-2-targeted therapy with enhanced cancer selectivity.
• To create antibodies that specifically recognize the activated form of Trop-2 found on cancer cells.

Main Methods:

• Deletion mutagenesis to remove the immunodominant epitope on Trop-2.
• Selection of cancer-specific, glycosylation-prone monoclonal antibodies (mAbs) using various binding assays.
• Humanization of the lead antibody (2G10) to generate Hu2G10.
• In vivo studies in mouse models of breast, colon, and prostate cancer.

Main Results:

• The 2G10 mAb family demonstrated selective binding to activated Trop-2 on cancer cells, not on normal cells.
• Hu2G10 exhibits high affinity for cleaved/activated Trop-2 (Kd < 10-12 mol/L) and low affinity for wild-type Trop-2 (Kd 3.16×10-8 mol/L).
• Hu2G10 effectively inhibited tumor growth in vivo without systemic toxicity.

Conclusions:

• Hu2G10 represents a novel therapeutic antibody with an unprecedented therapeutic index for Trop-2-targeted therapy.
• This approach offers a potential paradigm shift in treating Trop-2-expressing advanced cancers.
• Selective targeting of activated Trop-2 may overcome the limitations of current therapies.