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Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction
Published on: September 14, 2018
TROP2 antibody-drug conjugate: unique epitope engagement drives differentiated efficacy
Hang Chen1, Xiaoshan Min1, Qingwen Cheng1
1RemeGen Biosciences, Inc., 650 Gateway Blvd, Suite 110, South San Francisco, CA 94080, United States.
Background:
Trophoblast cell surface antigen 2 (TROP2) is frequently overexpressed in various cancers and is associated with poor prognosis. While TROP2-targeted antibody-drug conjugates (ADCs), such as sacituzumab govitecan, sacituzumab tirumotecan, and datopotamab deruxtecan (DXD), achieved clinical success, the mechanisms underlying resistance to these therapies remain incompletely understood. Consequently, the full therapeutic potential of TROP2 ADCs has yet to be comprehended.
Methods:
We developed R7059-DXD, a novel TROP2-targeted ADC featuring an antibody that binds an epitope that is distinct from those recognized by sacituzumab and datopotamab. The structural basis of epitope recognition was elucidated using cryo-electron microscopy (cryo-EM), complemented by binding affinity analyses across multiple surface-expressed TROP2 variants. Functional activity was systematically evaluated through in vitro antibody-dependent cellular cytotoxicity (ADCC) assays, in vitro ADC-mediated killing assays, and in vivo efficacy studies in tumor models, including resistant lines.
Results:
The R7059 antibody exhibited high binding affinity across multiple TROP2 variants, addressing a key resistance mechanism. The cryo-EM structure analysis revealed that the R7059 epitope lies in the N-terminal domain of TROP2 and is distinct from the sacituzumab and datopotamab epitopes. Functionally, R7059 demonstrated potent antitumor activity through both ADCC-dependent and independent mechanisms, suggesting additional signaling effects. The R7059 ADC demonstrated robust efficacy in multiple preclinical tumor models, including those resistant to approved TROP2 ADCs.
Conclusions:
R7059-DXD is a differentiated, epitope-distinct TROP2-targeted ADC with the potential to overcome resistance to existing therapies. These findings support its further clinical development as a novel treatment for TROP2-expressing malignancies, including in patients previously treated with sacituzumab- or datopotamab-based regimens.
Insights
A new TROP2-targeted antibody-drug conjugate, R7059-DXD, shows promise in overcoming resistance to current cancer therapies. Its unique epitope binding and potent antitumor activity support further clinical development for TROP2-expressing cancers.
Area of Science:
- Oncology
- Immunology
- Structural Biology
Background:
- Trophoblast cell surface antigen 2 (TROP2) is overexpressed in many cancers, correlating with poor prognosis.
- Existing TROP2-targeted antibody-drug conjugates (ADCs) show clinical success but face resistance, limiting their full therapeutic potential.
Purpose of the Study:
- To develop and characterize a novel TROP2-targeted ADC, R7059-DXD, designed to overcome resistance mechanisms.
- To elucidate the structural basis of R7059 binding and evaluate its functional efficacy.
Main Methods:
- Developed R7059-DXD, an ADC with an antibody targeting a distinct TROP2 epitope.
- Utilized cryo-electron microscopy (cryo-EM) for structural analysis and binding affinity assays.
- Assessed functional activity via in vitro ADCC and ADC-mediated killing assays, and in vivo efficacy studies in resistant tumor models.
Main Results:
- R7059 demonstrated high binding affinity across TROP2 variants, addressing a key resistance mechanism.
- Cryo-EM revealed the R7059 epitope is distinct from those targeted by sacituzumab and datopotamab.
- R7059-DXD exhibited potent antitumor activity through ADCC-dependent and independent mechanisms, showing efficacy in preclinical models resistant to approved TROP2 ADCs.
Conclusions:
- R7059-DXD is a novel TROP2 ADC with a distinct epitope, offering potential to overcome resistance to current therapies.
- Findings support R7059-DXD's clinical development for TROP2-expressing cancers, including in patients pre-treated with other TROP2 ADCs.
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