Session: 625. Lymphoma: Pre-Clinical—Chemotherapy and Biologic Agents: Poster III
TRPH-222 is an ADC comprised of an anti-CD22 antibody site-specifically modified at one site in each heavy chain to express formylglycine (FG), allowing for site-specific conjugation of a maytansinoid payload, a protease-insensitive spacer, and a functional group for coupling to an aldehyde on the antibody FG residues. This SMARTAG™ site specific non-cleavable conjugation enforces a maximum drug to antibody ratio (DAR) of 2.0.
The aim of this study was to characterize the anti-tumor activity of TRPH-222 in mouse xenografts and tolerability in non-human primates (NHP).
In the WSU-DLCL2 xenograft model, once weekly intravenous (IV) dosing of 1, 3 or 10mg/kg or TRPH-222 reduced tumor volume by 51%, 100% and 100% after 28 days. A once every three-week dose of 10mg/kg reduced tumor volume by 100% from pre-dosing measurements. In contrast, rituximab (30mg/kg, weekly) resulted in 55% tumor growth inhibition. In both SU-DHL-2 (DLBCL) and Granta-519 (MCL) xenograft models, weekly dosing at 10mg/kg resulted in tumor stasis.
The tolerability and PK of TRPH-222 were evaluated in cynomolgus monkeys. Animals were dosed IV once every 3 weeks (the anticipated clinical dosing schedule) for either 2 (5, 12.5, or 25 mg/kg) or 3 (50 mg/kg) doses. TRPH-222 was well tolerated at all doses evaluated and all animals survived to study termination, with no TRPH-222-related effects on clinical observations or body weight. Aspartate aminotransferase (AST) activity was mildly increased in animals at ≥12.5 mg/kg/dose, while minimal increases in alanine aminotransferase (ALT) activity were noted at 50 mg/kg/dose. Minor microscopic findings of Kupffer cell hypertrophy/hyperplasia were noted in the livers of monkeys treated at 50 mg/kg IV; this finding was not considered adverse based on minimal severity and lack of degeneration/necrosis. Preliminary PK data demonstrate the stability of TRPH-222, as the ratio of the area under the curve (AUC) from day 0-42 for the ADC was ~76-88% that of the antibody backbone suggesting that the ADC has a long half-life and that the linker is stable in vivo.
In conclusion, the studies reported here demonstrate that TRPH-222 has significant anti‑tumor activity in a range of B-cell lymphoma models and that very high doses of TRPH-222 are well tolerated in monkeys. IND-enabling safety studies are ongoing to support clinical evaluation of TRPH-222 in 2018. These data support the argument that TRPH-222 will have a large therapeutic window due to the stability of conjugation of the maytansinoid payload to the anti-CD22 antibody; doses tolerated in the monkey study described above correspond to human equivalent doses significantly higher than for most ADCs approved or currently under clinical evaluation. To our knowledge, this is the highest dose of a maytansine containing ADC that has been tolerated in monkeys and raises the potential for a best in class therapy for NHL in addition to a best in class ADC technology.
Disclosures: Maclaren: Triphase Accelerator: Employment. Levin: Triphase Accelerator: Employment. Lowman: Triphase Accelerator: Employment. Trikha: Triphase Accelerator: Employment; Encycle Therapeutics: Membership on an entity's Board of Directors or advisory committees.
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