Vincerx Pharma Presents Preclinical Data on VIP236, a First-in-Class Small Molecule Drug Conjugate (SMDC), at the 2023 American Association for Cancer Research (AACR) Annual Meeting
VIP236 is a first-in-class SMDC with a tailored design to efficiently treat patients with aggressive and metastatic cancer. VIP236 binds to activated αVβ3 integrin, allowing specific homing to the tumor, and is efficiently cleaved by neutrophil elastase (NE). Both proteins are present in the tumor microenvironment (TME), are highly expressed in advanced metastatic tumors, and are associated with poor prognosis. Anticancer activity occurs after a specific and targeted release of an optimized CPT payload by NE in the TME. Once the optimized CPT payload penetrates and accumulates in the cell, it inhibits topoisomerase 1 (TOP1), causing DNA damage and leading to cell death. The novel optimized CPT payload of VIP236 was designed for high permeability with low active efflux potential to overcome transporter-mediated resistance observed with SN38, the active metabolite of irinotecan, which is also a CPT.
“The preclinical data presented at AACR demonstrate that VIP236 had potent and durable antitumor activity in multiple mouse models implanted with tumor cells from cancer patients,” said Ahmed Hamdy M.D., Chief Executive Officer of Vincerx. “VIP236 treatment was efficacious in a PDX non-small cell lung cancer model, including durable complete responses (CRs). Additionally, we observed significant tumor growth inhibition in a PDX colorectal cancer (CRC) liver metastasis model and significantly reduced lung and brain metastasis in a PDX orthotopic triple negative breast cancer (TNBC) model. Most notably, in gastric PDX and cell line-derived cancer models, VIP236 showed significant tumor growth inhibition compared with ENHERTU®, an approved antibody-drug conjugate (ADC), independent of HER2 status. We know ENHERTU works in HER2 low breast cancer, so we’re encouraged to see our SMDC showing improved in vivo efficacy not just in HER2 high but also in HER2 low and HER2 negative gastric models. It’s important to note that showing this type of activity in PDX models is impressive, since these models are representative of the heterogeneity of human cancer and more meaningful than results seen in cell lines.”
Key Presentation Highlights:
Poster presentation, titled, VIP236: A small molecule drug conjugate with an optimized camptothecin payload has significant activity in patient-derived and metastatic cancer models, presented by Beatrix Stelte-Ludwig, Ph.D.,
- In an orthotopic metastatic breast cancer PDX model, immunohistochemistry analysis revealed an increase of αvβ3 and elastase staining after VIP236 treatment, while TOP1 expression remained stable. These results suggest VIP236 has potential antineoplastic activity across various advanced and metastatic cancers.
- The mechanism of action of VIP236’s optimized CPT is characterized by TOP1 inhibition, which leads to DNA damage and, ultimately, cell death. DNA damage can be measured by phosphorylation of ɣH2Ax.
- Time- and treatment-dependent phosphorylation of ɣH2Ax cells from the SNU16 cell line derived mouse model confirmed on-target TOP1 inhibition from the liberated optimized CPT payload derived from VIP236 and subsequent DNA damage.
- VIP236 was efficacious in a PDX non-small cell lung cancer (NSCLC) model, with durable CRs. Partial responses and stable diseases were observed in PDX colon, renal, and TNBC models. Additionally, VIP236 treatment induced significant tumor growth inhibition in a PDX CRC liver metastatic model and significant reduction in lung and brain metastasis in a PDX orthotopic TNBC model. The reduction of brain metastases suggests successful VIP236 penetration of the blood-brain barrier.
- In gastric PDX cancer models, VIP236 treatment showed significant tumor growth inhibition compared with the approved anti-HER2 ADC, ENHERTU® (trastuzumab deruxtecan), independent of HER2 expression levels. Similar results were observed in a cell line-derived mouse model (HER2neg SNU16).
- VIP236 is currently being evaluated in a first-in-human Phase 1 dose-escalation study in patients with advanced solid tumors (NCT05712889).
The poster can be accessed on the presentations section of the Vincerx website.
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Source: Vincerx Pharma, Inc.