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4105 Trph-222, a Novel Anti-CD22 Antibody Drug Conjugate (ADC), Has Signficant Anti-Tumor Activity in NHL Xenografts and Is Well Tolerated in Non-Human Primates

Program: Oral and Poster Abstracts
Session: 625. Lymphoma: Pre-Clinical—Chemotherapy and Biologic Agents: Poster III
Monday, December 11, 2017, 6:00 PM-8:00 PM
Bldg A, Lvl 1, Hall A2 (Georgia World Congress Center)

Ann Maclaren, PhD, BS*, Nancy Levin, PhD*, Henry Lowman, PhD* and Mohit Trikha, PhD

Triphase Accelerator, La Jolla, CA

CD22 is a B-cell specific transmembrane glycoprotein belonging to the SIGLEC family of lectins. Its expression is restricted to B lineage cells from the early immature/pre-B-cell stage through the mature naïve stage, and is downregulated on the surface of plasma cells. CD22 is highly expressed on a wide range of malignancies arising from mature B-cells, including NHL (non-Hodgkin’s lymphoma), DLBCL (diffuse large B cell lymphoma), MCL (mantle cell lymphoma), MZL, B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia and small lymphocytic leukemia. The restricted lineage of CD22 and rapid internalization upon antibody binding make CD22 an appealing target for an antibody-drug conjugate (ADC) therapeutic for B cell malignancies. Prior attempts at targeting CD22 using ADC technology have been limited clinically in NHL due to an unacceptable or poor therapeutic index. Subsequently the ADC field has focused on more stable and site specific conjugation of payloads to increase the therapeutic index of ADCs.

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.

*signifies non-member of ASH