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Glutamic acid-valine-citrulline linkers ensure stability and efficacy of antibody-drug conjugates in mice.

ABSTRACT: Valine-citrulline linkers are commonly used as enzymatically cleavable linkers for antibody-drug conjugates. While stable in human plasma, these linkers are unstable in mouse plasma due to susceptibility to an extracellular carboxylesterase. This instability often triggers premature release of drugs in mouse circulation, presenting a molecular design challenge. Here, we report that an antibody-drug conjugate with glutamic acid-valine-citrulline linkers is responsive to enzymatic drug release but undergoes almost no premature cleavage in mice. We demonstrate that this construct exhibits greater treatment efficacy in mouse tumor models than does a valine-citrulline-based variant. Notably, our antibody-drug conjugate contains long spacers facilitating the protease access to the linker moiety, indicating that our linker assures high in vivo stability despite a high degree of exposure. This technology could add flexibility to antibody-drug conjugate design and help minimize failure rates in pre-clinical studies caused by linker instability.

SUBMITTER: Anami Y

PROVIDER: S-EPMC6023893 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Glutamic acid-valine-citrulline linkers ensure stability and efficacy of antibody-drug conjugates in mice.

Anami Yasuaki Y Yamazaki Chisato M CM Xiong Wei W Gui Xun X Zhang Ningyan N An Zhiqiang Z Tsuchikama Kyoji K

Nature communications 20180628 1

Valine-citrulline linkers are commonly used as enzymatically cleavable linkers for antibody-drug conjugates. While stable in human plasma, these linkers are unstable in mouse plasma due to susceptibility to an extracellular carboxylesterase. This instability often triggers premature release of drugs in mouse circulation, presenting a molecular design challenge. Here, we report that an antibody-drug conjugate with glutamic acid-valine-citrulline linkers is responsive to enzymatic drug release but ...[more]

PMID: 29955061

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Project description:BackgroundBoth ganglioside GD2-targeted immunotherapy and antibody-drug conjugates (ADCs) have demonstrated clinical success as solid tumor therapies in recent years, yet no research has been carried out to develop anti-GD2 ADCs against solid tumors. This is the first study to analyze cytotoxic activity of clinically relevant anti-GD2 ADCs in a wide panel of cell lines with varying GD2 expression and their effects in mouse models of GD2-positive solid cancer.MethodsAnti-GD2 ADCs were generated based on the GD2-specific antibody ch14.18 approved for the treatment of neuroblastoma and commonly used drugs monomethyl auristatin E (MMAE) or F (MMAF), conjugated via a cleavable linker by thiol-maleimide chemistry. The antibody was produced in a mammalian expression system, and its specific binding to GD2 was analyzed. Antigen-binding properties and biodistribution of the ADCs in mice were studied in comparison with the parent antibody. Cytotoxic effects of the ADCs were evaluated in a wide panel of GD2-positive and GD2-negative tumor cell lines of neuroblastoma, glioma, sarcoma, melanoma, and breast cancer. Their antitumor effects were studied in the B78-D14 melanoma and EL-4 lymphoma syngeneic mouse models.ResultsThe ch14.18-MMAE and ch14.18-MMAF ADCs retained antigen-binding properties of the parent antibody. Direct dependence of the cytotoxic effect on the level of GD2 expression was observed in cell lines of different origin for both ADCs, with IC50 below 1 nM for the cells with high GD2 expression and no cytotoxic effect for GD2-negative cells. Within the analyzed cell lines, ch14.18-MMAF was more effective in the cells overexpressing GD2, while ch14.18-MMAE had more prominent activity in the cells expressing low GD2 levels. The ADCs had a similar biodistribution profile in the B78-D14 melanoma model compared with the parent antibody, reaching 7.7% ID/g in the tumor at 48 hours postinjection. The average tumor size in groups treated with ch14.18-MMAE or ch14.18-MMAF was 2.6 times and 3.8 times smaller, respectively, compared with the control group. Antitumor effects of the anti-GD2 ADCs were also confirmed in the EL-4 lymphoma model.ConclusionThese findings validate the potential of ADCs targeting ganglioside GD2 in treating multiple GD2-expressing solid tumors.

Dataset Information

Glutamic acid-valine-citrulline linkers ensure stability and efficacy of antibody-drug conjugates in mice.

Publications

Glutamic acid-valine-citrulline linkers ensure stability and efficacy of antibody-drug conjugates in mice.

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