Abstract 2186: Peptide-cleavable maytansinoid (ADCs) induce high bystander killing leading to improved anti-tumor activityin vivo

Antibodies targeting surface antigens on cancer cells typically have progressively lower access to tumor cells that are further removed from blood vessels. Also, the antibody will not bind to cells in the tumor mass that do not express antigen, including stromal cells of the tumor, many of which reportedly aid in the survival or metastasis of cancer cells. ADCs can bind to antigen positive cancer cells, after which they are internalized and catabolized to release one or more cytotoxic metabolite(s) that can kill the targeted cell. Metabolites that are membrane permeable may also diffuse into and kill neighboring cells, often called bystander cells, that would normally be less accessible. The goal of this work was to design ADCs that would have increased bystander activity, which could result in greater killing of cancer cells and stromal cells in the tumor environment. We have prepared a new type of peptide-cleavable immolative ADC (PCI-ADC) that efficiently releases membrane permeable cytotoxic maytansinoid metabolites upon cleavage of the peptide linker, followed by immolation. Several PCI-ADCs were prepared that release metabolites having different degrees of hydrophobicity. As the hydrophobicity of the metabolite increased, the PCI-ADCs’ bystander activity also increased. The lead PCI-ADC generally displayed a similar degree of in vitro cytotoxicity as maytansinoid ADCs that utilize disulfide linkers, however the PCI-ADC induced significantly more bystander killing. In mice bearing large tumor xenografts (250 mm3) or tumor xenografts that express the target antigen heterogeneously, PCI-ADCs were found to be more efficacious than maytansinoid ADCs that use disulfide linkers, as well as our recently reported peptide-para-anilino maytansinoid ADCs. The nature of the amino acid residues in the peptide linker of the PCI-ADC was also altered so that the tolerability of the ADCs in mice could be increased without impeding efficacy. In conclusion, we have developed a promising new type of maytansinoid ADC, one that provides a high degree of bystander killing, improved activity in homogeneous and heterogeneous tumor models in vivo, and has a different mechanism of metabolite release than current maytansinoid based ADCs. Citation Format: Wayne C. Widdison, Juliet A. Costoplus, Jose F. Ponte, Leanne Lanieri, Yulius Setiady, Ling Dong, Anna Skaletskaya, Rui Wu, Qifeng Qiu, Yelena Kovtun, Ravi V. Chari. Peptide-cleavable maytansinoid (ADCs) induce high bystander killing leading to improved anti-tumor activity in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2186. doi:10.1158/1538-7445.AM2017-2186