An Antibody-Drug Conjugate Targeting MUC1-Associated Carbohydrate CA6 Shows Promising Antitumor Activities
Céline Nicolazzi1, Anne Caron2, Alexia Tellier2
1Sanofi R&D, Vitry-sur-Seine, France. celine.nicolazzi@sanofi.com.
Abstract:
Glycosylation is a complex multienzyme-related process that is frequently deregulated in cancer. Aberrant glycosylation can lead to the generation of novel tumor surface-specific glycotopes that can be targeted by antibodies. Murine DS6 mAb (muDS6) was generated from serous ovary adenocarcinoma immunization. It recognizes CA6, a Mucin-1 (MUC1)-associated sialoglycotope that is highly detected in breast, ovarian, lung, and bladder carcinomas. SAR566658 antibody-drug conjugate (ADC) is a humanized DS6 (huDS6) antibody conjugated through a cleavable linker to the cytotoxic maytansinoid derivative drug, DM4. SAR566658 binds to tumor cells with subnanomolar affinity, allowing good ADC internalization and intracellular delivery of DM4, resulting in tumor cell death (IC50 from 1 to 7.3 nmol/L). SAR566658 showed in vivo antitumor efficacy against CA6-positive human pancreas, cervix, bladder, and ovary tumor xenografts and against three breast patient-derived xenografts. Tumor regression was observed in all tumor models with minimal effective dose correlating with CA6 expression. SAR566658 displayed better efficacy than standard-of-care nontargeted tubulin binders. These data support the development of SAR566658 in patients with CA6-expressing tumors.
Insights
The novel antibody-drug conjugate SAR566658 targets the CA6 glycotopes on cancer cells. This conjugate demonstrated significant antitumor efficacy in preclinical models, supporting its development for CA6-expressing tumors.
Area of Science:
- Oncology
- Glycobiology
- Immunotherapy
Background:
- Aberrant glycosylation is a hallmark of cancer, creating unique tumor surface targets.
- The CA6 sialoglycotope, associated with Mucin-1 (MUC1), is highly expressed in various carcinomas.
- Murine DS6 mAb (muDS6) targets the CA6 glycotopes.
Purpose of the Study:
- To evaluate the antitumor efficacy of SAR566658, an antibody-drug conjugate (ADC) targeting CA6.
- To assess the potential of SAR566658 as a targeted therapy for CA6-expressing cancers.
Main Methods:
- SAR566658 is a humanized DS6 (huDS6) antibody conjugated to DM4 via a cleavable linker.
- In vitro cytotoxicity was assessed (IC50 values).
- In vivo antitumor efficacy was evaluated in xenograft models of pancreas, cervix, bladder, ovary, and breast cancers.
Main Results:
- SAR566658 exhibited potent binding to tumor cells (subnanomolar affinity) and effective intracellular drug delivery.
- Significant tumor regression was observed across multiple CA6-positive xenograft models.
- Efficacy correlated with CA6 expression and surpassed standard-of-care tubulin binders.
Conclusions:
- SAR566658 demonstrates promising preclinical antitumor activity against CA6-expressing tumors.
- The targeted approach of SAR566658 offers a potential new therapeutic strategy.
- Further clinical development of SAR566658 for CA6-positive cancers is warranted.
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