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Branched pegylated linker-auristatin to control hydrophobicity for the production of homogeneous minibody-drug conjugate against HER2-positive breast cancer
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International audience. Trastuzumab emtansine (Kadcyla®) was the first antibody-drug conjugate (ADC) approved by the Food and DrugAdministration in 2013 against a solid tumor, and the first ADC to treat human epidermal growth factor receptor2 positive (HER2+) breast cancer. However, this second generation ADC is burden by several limitationsincluded heterogeneity, limited activity against heterogeneous tumor (regarding antigen expression) and suboptimaltumor penetration. To address this, different development strategies are oriented towards homogeneousconjugation, new drugs, optimized linkers and/or smaller antibody formats. To reach better developed nextgeneration ADCs, a key parameter to consider is the management of the hydrophobicity associated with thelinker-drug, increasing with and limiting the drug-to-antibody ratio (DAR) of the ADC. Here, an innovativebranched pegylated linker was developed, to control the hydrophobicity of the monomethyl auristatin E (MMAE)and its cathepsin B-sensitive trigger. This branched pegylated linker-MMAE was then used for the efficientgeneration of internalizing homogeneous ADC of DAR 8 and minibody-drug conjugate of DAR 4, targeting HER2.Both immunoconjugates were then evaluated in vitro and in vivo on breast cancer models. Interestingly, this studyhighlighted that the minibody-MMAE conjugate of DAR 4 was the best immunoconjugate regarding in vitrocellular internalization and cytotoxicity, gamma imaging, ex vivo biodistribution profile in mice and efficientreduction of tumor size in vivo. These results are very promising and encourage us to explore further fragmentdrugconjugate development.
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