Novel Peptide Camptothecin Drug-linkers for Potent ADCs—Letter

We respond to the article by Lyski and colleagues (1) in the December 3 online edition of the journal because of the comparison between the article's antibody–drug conjugates (ADC) and a complementary ADC incorporating our linker payload, CL2A-SN-38, which the authors refer to as “GT.” While we have shown specificity for our ADCs versus non-specific ADC controls in several tumor xenograft models (2–5), which the authors overlooked, specificity in vitro was not observed. We reported previously that this is likely due to the hydrolysable nature of the linker and the 96-hour assay timeframe which would result in the release of the coupled SN-38, the active principle of camptothecin, thereby making specificity impossible to show under these conditions. However, specificity was reported initially using a different assay with shorter incubation periods (5), and later in studies that also documented bystander killing of antigen-negative tumor cells due to extracellular release of SN-38 [e.g., Lopez and colleagues (6)].

Regarding the activity of SN-38 conjugates in vivo, it should be noted that SN-38 conjugates are well tolerated, and therefore amenable administration in repeated cycles of therapy, which is conducive for the cell cycle–dependent activity of SN-38. This repeated cycle approach has been successful in multiple clinical trials and indications (7).

Therefore, we submit that the head-to-head comparison of conventional ADCs, which follow the paradigm of using ultrapotent cytotoxic payloads and strictly intracellularly cleavable linkers, with our ADCs, whose design is different, is not useful in the preclinical setting, because the dose and dose schedule are distinctly different. Ultimately, the therapeutic index is key, and any comparison is meaningful when made in the clinical setting for the same disease indication.

We are gratified to note that the article's ADC design utilizes a short PEG and lysine combination as part of the linker, which we introduced in our early studies to enable high drug substitution with a high monomeric ADC profile [low dimer or aggregation (8)], and which we believe defines a third-generation platform for ADCs (7).

We congratulate the authors for exploring a topoisomerase I inhibitor as an ADC payload. Such advances auger well for patients by providing more potential options for advancing the ADC field.

See the Response, p. 238