Effects of linker chemistry on tumor targeting by anti-CD70 antibody-drug conjugates Free

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h1F6 is a mAb that recognizes CD70, an antigen found on a variety of solid and hematologic tumors. While antibody-drug conjugates (ADCs) can take advantage of the ability of the mAb to localize to tumors, the nature of the drug and the linker can also play a role in the effectiveness of tumor targeting. Monomethyl auristatin F (MMAF), a potent anti-mitotic agent, was linked to h1F6 through a protease sensitive valine-citrulline linker (vcMMAF) or a maleimidocaproyl linker (mcMMAF) that lacks the protease sensitive peptide spacer. The choice of linker influences the composition of the released drug, and plays a role in the potency and tolerability of the ADC. The efficacy of h1F6-vcMMAF and -mcMMAF ADCs were evaluated in CD70-positive subcutaneous and orthotopic xenograft models. It was observed that both ADCs could yield tumor growth delays and complete regressions. Although h1F6-vcMMAF was more potent than h1F6-mcMMAF, it was also tolerated at much lower doses. This demonstrates that changing the structure of the drug linker affects both efficacy and the therapeutic index. The amount of drug that accumulates in tumors and tissues was measured with vcMMAF and mcMMAF ADCs containing tritium-labeled drug. Animals bearing CD70-positive xenografts were dosed with these ADCs, and tumors and tissues harvested at various time points. While the intratumoral drug concentration achieved by h1F6-mcMMAF was slightly lower than by h1F6-vcMMAF, the tumor to tissue ratios were much higher. Thus, the mode of drug attachment and the nature of the released drug can have a pronounced effect on in vivo ADC activity.