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Linker stability influences the anti-tumor activity of acetazolamide-drug conjugates for the therapy of renal cell carcinoma.

ABSTRACT: Small molecule-drug conjugates (SMDCs) are increasingly being considered as an alternative to antibody-drug conjugates (ADCs) for the selective delivery of anticancer agents to the tumor site, sparing normal tissues. Carbonic anhydrase IX (CAIX) is a membrane-bound enzyme, which is over-expressed in the majority of renal cell carcinomas and which can be efficiently targeted in vivo, using charged derivatives of acetazolamide, a small heteroaromatic sulfonamide. Here, we show that SMDC products, obtained by the coupling of acetazolamide with monomethyl auristatin E (MMAE) using dipeptide linkers, display a potent anti-tumoral activity in mice bearing xenografted SKRC-52 renal cell carcinomas. A comparative evaluation of four dipeptides revealed that SMDCs featuring valine-citrulline and valine-alanine linkers exhibited greater serum stability and superior therapeutic activity, compared to the counterparts with valine-lysine or valine-arginine linkers. The most active products substantially inhibited tumor growth over a prolonged period of time, in a tumor model for which sunitinib and sorafenib do not display therapeutic activity. However, complete tumor eradication was not possible even after ten intravenous injection. Macroscopic near-infrared imaging procedures confirmed that ligands had not lost the ability to selectively localize at the tumor site at the end of therapy and that the neoplastic masses continued to express CAIX. The findings are of mechanistic and of therapeutic significance, since CAIX is a non-internalizing membrane-associated antigen, which can be considered for targeted drug delivery applications in kidney cancer patients.

SUBMITTER: Cazzamalli S

PROVIDER: S-EPMC5266555 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Linker stability influences the anti-tumor activity of acetazolamide-drug conjugates for the therapy of renal cell carcinoma.

Cazzamalli Samuele S Corso Alberto Dal AD Neri Dario D

Journal of controlled release : official journal of the Controlled Release Society 20161124

Small molecule-drug conjugates (SMDCs) are increasingly being considered as an alternative to antibody-drug conjugates (ADCs) for the selective delivery of anticancer agents to the tumor site, sparing normal tissues. Carbonic anhydrase IX (CAIX) is a membrane-bound enzyme, which is over-expressed in the majority of renal cell carcinomas and which can be efficiently targeted in vivo, using charged derivatives of acetazolamide, a small heteroaromatic sulfonamide. Here, we show that SMDC products, ...[more]

PMID: 27890855

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Project description:Charge variants are important attributes of monoclonal antibodies, including antibody-drug conjugates (ADCs), because charge variants can potentially influence the stability and biological activity of these molecules. Ion exchange chromatography (IEX) is widely used for charge variants analysis of mAbs and offers the feasibility of fractionation for in-depth characterization. However, the conjugated linker-drug on ADCs could potentially affect the separation performance of IEX, considering IEX separation relies on surface charge distribution of analyte and involves the interaction between analyte surface and IEX stationary phase. Here, we investigated weak cation exchange chromatography (WCX) for its application in analyzing three ADCs (two broad distribution ADCs and an ADC with controlled conjugation sites) and the 2-drug/4-drug loaded species isolated from the two broad distribution ADCs using hydrophobic interaction chromatography. The major peaks in WCX profile were characterized via fraction collection followed by capillary electrophoresis-sodium dodecyl sulfate or peptide mapping. Results suggested that both the number of drug loads and conjugation sites could impact WCX separation of an ADC. The hypothesis was that the linker drugs could interfere with the ionic interaction between its surrounding amino acids on the mAb surface and column resin, which reduced the retention of ADCs on WCX column in this study. Our results further revealed that WCX brings good selectivity towards positional isomers, but limited resolution for different drug load, which causes the peak compositions of the two broad-distribution ADCs to be highly complex. We also compared results from WCX and imaged capillary isoelectric focusing (icIEF). Results showed that separation in icIEF was less influenced by conjugated linker drugs for the ADCs studied in this work, and better alignment was found between the two techniques for the ADC with controlled conjugate sites. Overall, this work provides insights into the complexity of WCX analysis of ADCs, which should be considered during method development and sample characterization.

Dataset Information

Linker stability influences the anti-tumor activity of acetazolamide-drug conjugates for the therapy of renal cell carcinoma.

Publications

Linker stability influences the anti-tumor activity of acetazolamide-drug conjugates for the therapy of renal cell carcinoma.

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