Vincerx Pharma Presents Preclinical Data on Novel Small Molecule Drug Conjugates at the American Association for Cancer Research (AACR) Annual Meeting 2023
Vincerx’s next-generation modular bioconjugation platform is designed to effectively target tumors with different modalities, including SMDCs and antibody-drug conjugates (ADCs). Our next-generation bioconjugation technology overcomes many of the known challenges of first-generation conjugation platforms and has shown increased safety and efficacy in relevant whole animal models. The platform consists of novel linker chemistries for tumor specific payload release; a toolbox of potent payload classes with novel modes of action to address a broad range of cancer targets; and tunable features that allow for optimization of the payload’s physiochemical profile to match target tumor biology.
“The preclinical data presented at AACR demonstrate our ability to synthesize and characterize novel SMDCs,” said
Key Presentation Highlights:
Poster presentation, titled, Synthesis and characterization of novel small molecule drug conjugates with different payloads designed to be released in tumor microenvironment by neutrophil elastase, presented by
- Imaging studies with fluorescent conjugates indicate efficient tumor homing in the tumor microenvironment of the αvβ3 binder and tumor-associated cleavage by neutrophil elastase (NE).
- An optimized camptothecin (CPT; topoisomerase inhibitor), P-TEFbi (CDK9/CycT inhibitor) and kinesin spindle protein inhibitor (KSPi) were successfully converted into αvβ3-targeted SMDCs (VIP550, VIP280, and VIP1339, respectively) using different chemical handles (alcohol, sulfoximine and primary amine).
- NE-cleavable linkers show high elastase-dependent potency with IC50 values of αvβ3 conjugates VIP550, VIP280 and VIP1339 in the nanomolar range across several cancer cell lines (786-0, HT29, NCI-H292, and SUM149) reaching similar potency as compared with the respective payloads alone.
- αvβ3 conjugates VIP280, VIP550 and VIP1339 demonstrated excellent plasma stability and elastase-mediated release of CPT, P-TEFbi and KSPi payloads in rat plasma as well as in buffer at pH7.4.
- Plasma clearance of all 3 small molecule drug αvβ3 conjugates was low with clearance being in the following rank ordering: VIP1339 > VIP550 > VIP280. Half-life was longer for SMDCs with the lowest clearance estimates. The ratio between AUC of the payload and parent SMDC was decreasing in the order of VIP280 > VIP550 > VIP1339. A 15-fold reduction in this ratio between VIP280 and VIP550 suggest a large increase in in vivo stability of the payload linker for VIP550 compared with VIP280.
- Strong in vivo efficacy was shown with the SMDC VIP550 with a CPT payload in the MX1 TNBC mouse model. VIP550 monotherapy exhibits tumor regression in the 20 mg/kg intravenous 2 days on/5 days off treatment schedule (PR: 12/12). Once weekly application of VIP550 achieved stable disease (
T/C: 0.34) and was slightly less efficacious compared with VIP236 ( T/C: 0.24). No significant impact on mean body weight of mice was observed, indicating good tolerability of VIP550 and VIP236.
The poster can be accessed on the presentations section of the Vincerx website.
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Source: Vincerx Pharma, Inc.