Abstract
Simple SummaryMany cancer drugs are cytotoxic, which means that they kill cancer cells effectively but are also toxic to normal cells. To overcome this problem, we designed a novel compound, VIP236, which consists of three components. The first part enables the drug to target and bind to a protein called ‘αVβ3 integrin’ on the surface of cancer cells. The second part is a new cytotoxic drug, VIP126. The third component links the two parts together and can only be sliced by the enzyme neutrophil elastase. Neutrophil elastase is found in high quantities in tumors, ensuring that VIP126 is released near the cancer cells and less around normal cells. VIP126, when delivered as a component of VIP236, kills tumor cells in mouse cancer models without the toxicity seen with standard chemotherapy. VIP236 may be a new modality for targeting cancer cells directly, while reducing the harmful effects to normal tissue.To improve tumor selectivity of cytotoxic agents, we designed VIP236, a small molecule–drug conjugate consisting of an αVβ3 integrin binder linked to a modified camptothecin payload (VIP126), which is released by the enzyme neutrophil elastase (NE) in the tumor microenvironment (TME). The tumor targeting and pharmacokinetics of VIP236 were studied in tumor-bearing mice by in vivo near-infrared imaging and by analyzing tumor and plasma samples. The efficacy of VIP236 was investigated in a panel of cancer cell lines in vitro, and in MX-1, NCI-H69, and SW480 murine xenograft models. Imaging studies with the αVβ3 binder demonstrated efficient tumor targeting. Administration of VIP126 via VIP236 resulted in a 10-fold improvement in the tumor/plasma ratio of VIP126 compared with VIP126 administered alone. Unlike SN38, VIP126 is not a substrate of P-gp and BCRP drug transporters. VIP236 presented strong cytotoxic activity in the presence of NE. VIP236 treatment resulted in tumor regressions and very good tolerability in all in vivo models tested. VIP236 represents a novel approach for delivering a potent cytotoxic agent by utilizing αVβ3 as a targeting moiety and NE in the TME to release the VIP126 payload—designed for high permeability and low efflux—directly into the tumor stroma.
Highlights
IntroductionTherapeutics designed to target cancer cells by conjugating cytotoxic agents to selective tumor-targeting molecules are a promising strategy for drug development
Therapeutics designed to target cancer cells by conjugating cytotoxic agents to selective tumor-targeting molecules are a promising strategy for drug development.Therapeutics designed to target cancer cells by conjugating cytotoxic agents to selective tumor-targeting molecules are a promising strategy for drug development
The IR800-coupled αV β3 integrin binder showed strong tumor homing in 786-O renal cell carcinoma (RCC) tumor-bearing mice (Figure 2A), whereas no tumor-specific accumulation was detected with the non-binding IR800-coupled control conjugate (Figure 2B)
Summary
Therapeutics designed to target cancer cells by conjugating cytotoxic agents to selective tumor-targeting molecules are a promising strategy for drug development. Recent research interest has previously focused on antibody–drug conjugates (ADCs) that utilize antibodies to deliverfocused potent cytotoxic agents [1,2,3]. 10 years, Recent research interest has previously on antibody–drug conjugates that. 12 ADCstohave beenpotent approved for patient including utilize antibodies deliver cytotoxic agentstreatment,. In the past 10Adcetris years, altogether ® in ® in 2017. [4,5]; Kadcyla [6,7]; Besponsa [8]; MylotargTM (re-approval 2018)
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