Background and Purpose Antibody-drug conjugates (ADCs) represent a therapeutic modality that guides chemotherapies to tumoral cells by using antibodies against tumor associated antigens (TAAs). The antibody and the chemotherapy or payload are attached by a chemical structure called the linker. The strategy for the development of this type of drugs was based on several rational pillars, including the use of a very potent payload and the use of specific antibodies acting only on antigens expressed on tumoral cells. Experimental Approach In this article, by using data from all approved ADCs that have received regulatory approval, we explore the contribution of each ADC component to clinical activity. Key Results We have identified that the potency of the payload and its amount -evaluated by the drug to antibody ratio (DAR)- do not relate to clinical efficacy. Additionally, some ADCs have been developed against antigens expressed in non-transformed tissues producing clinical activity, suggesting that TAA specificity is not a mandatory requirement. Finally, we observed that ADCs with payloads harboring more favorable physicochemical characteristics showed the greater activity, and indeed were those that used linkers with site-specific conjugation. Conclusion and Implications Based on currently available data, our study provides insights as to the best way to develop novel ADCs in the future.

Familial Colorectal Cancer Type X (FCCTX) is a term used to describe a group of families with an increased predisposition to colorectal and other related cancers, but an unknown genetic basis. Whole-exome sequencing in two cancer-affected and one healthy members of a FCCTX family revealed a truncating germline mutation in PTPRT [c.4090dup, p.(Asp1364GlyfsTer24)]. PTPRT encodes a receptor phosphatase and is a tumor suppressor gene found to be frequently mutated at somatic level in many cancers, having been proven that these mutations act as drivers that promote tumor development. This germline variant shows a compatible cosegregation with cancer in the family and results in the loss of a significant fraction of the second phosphatase domain of the protein, which is essential for PTPRT’s activity. In addition, the tumors of the carriers exhibit epigenetic inactivation of the wild-type allele and an altered expression of PTPRT downstream target genes, consistent with a causal role of this germline mutation in the cancer predisposition of the family. Although PTPRT’s role cancer initiation and progression has been well studied, this is the first time that a germline PTPRT mutation is linked with cancer susceptibility and hereditary cancer, which highlights the relevance of the present study.