Abstract 3898: Preclinical evaluation of DM21, a next-generation maytansinoid payload with a stable peptide linker

Antibody drug conjugates (ADCs) are designed to target surface antigen(s) expressed at higher levels on cancer cells compared to normal cells. ADCs are internalized and the antibody component is subsequently degraded in catabolic vesicles to release cytotoxic metabolites that can kill the cell. Membrane permeable metabolites can also diffuse into and kill neighboring cells (also called bystander cells) via a mechanism known as bystander killing, resulting in greater tumor cell killing. Non-antigen-mediated mechanisms of antibody and ADC uptake are also known to occur, and the maximum tolerated dose for most ADCs is driven by target independent delivery. DM21 is a peptide-cleavable immolative maytansinoid payload that was designed to allow ADCs to efficiently release hydrophobic metabolites better than conjugates utilizing the disulfide linked maytansinoid DM4. DM21 ADCs typically have similar direct in vitro cytotoxicity as DM4 ADCs against antigen positive cells, but have much greater bystander killing activity in assays where antigen positive cells are mixed with antigen negative cells. To evaluate the toxicity of DM21 as an ADC, it was conjugated to the non-targeting, chimeric anti-soybean trypsin inhibitor antibody (chKTI), and administered to cynomolgus monkeys. Two groups of 5 male cynomolgus monkeys received a single intravenous dose of chKTI-DM21 at dose levels of 11 and 22 mg/kg (204 and 408 µg/kg DM21), while a concurrent group of 5 male monkeys was administered the formulation buffer as a control group. Three monkeys/group were sacrificed on Day 5 (terminal necropsy) to assess acute toxicity, and the remaining two monkeys/group were sacrificed on Day 29 (recovery necropsy) to assess the recovery, persistence, or progression of any effects. Toxicity was determined based upon clinical observations, body weights, ophthalmic examinations, and clinical and anatomic pathology. Plasma and serum samples were also collected to evaluate the toxicokinetic (TK) profile. chKTI-DM21 was well tolerated at both doses. There was no effect on body weight gain, and clinical observations were limited to reddened/darkened skin, scabbing, and soft/liquid feces. Effects noted on clinical pathology parameters included alterations in erythroid and leukocyte parameters, increased platelet counts and fibrinogen, and transient increases in ALT and AST without histopathologic correlates. The target organ noted at the terminal necropsy was the large intestine (cecum, colon, and rectum), but all findings were resolved by the recovery necropsy indicating reversibility. Toxicokinetic analysis of the samples showed that chKTI-DM21 has dose proportional exposure and apparent stability of the peptide linkage in cynomolgus plasma. In conclusion, DM21 is a promising maytansinoid payload with a high-degree of bystander activity and a favorable toxicity profile. Citation Format: Wayne Deats, Wayne Widdison, Juliet Costoplus, Bahar Matin, Nicole McBrine, Laura Bartle, Olga Ab, Richard Gregory, Jan Pinkas. Preclinical evaluation of DM21, a next-generation maytansinoid payload with a stable peptide linker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3898.