Abstract 710: Preclinical development of ALD2510, a Next-Gen Fc-enhanced, TREG-selective and IL-2-sparing anti-CD25 antibody for the treatment of solid tumors
Authors: Houacine Jemila , Abes Riad , Marie-Cardine Anne , Roy Aude Le , Serbin Bettina , Robert Lucie , Giustiniani Jérôme , Chrétien Anne-Sophie , Fattori Stéphane , Gorvel Laurent , Bensussan Armand , Olive Daniel , Foussat Arnaud 
Published: April 2023

Abstract
Within the tumor microenvironment (TME), TREGS have been associated with worse prognosis and/or resistance to checkpoint inhibitor (CPI) therapy in various cancer diseases, making these cells a promising target for the development of new immunotherapies. Here, we present recent preclinical development data about ALD2510, a next-gen low-fucose IL-2/TCONV-sparing anti-CD25 antibody designed for the selective depletion of CD25high TREGS and the boost of host anti-tumor immunity. Ultra-humanization of parental anti-CD25 antibody was achieved through phage display and, in parallel, all putative liability sequences were replaced for maximizing developability while minimizing off-target and immunogenicity risks. ALD2510 sequences were re-formatted and used for further CHO cell line development, using the GlymaxX™ technology which boosts Fc effector functions. Early tox ALD2510 material was produced following 10L fed-batch USP/DSP and analytical characterization, including a 6-month early stability study. Preliminary safety and pharmacokinetic/pharmacodynamic (PKPD) profile of ALD2510 were then determined through a non-GLP MTD/DRF study in cynomolgus monkey. ALD2510 demonstrated excellent potency (TREG depletion, ADCC, ADCP), manufacturability and stability together with very low immunogenicity potential. CHO productivity reached ~4g/L in 10L fed-batch bioreactor and characterization revealed excellent purity and activity in line with its low fucose content, together with very low levels of process- or cell-related impurities. This material showed a good behavior during the 6-month stability study and was therefore administered in cynomolgus monkeys during a non-GLP exploratory MTD/DRF study. Increasing doses of ALD2510 (from 0.3 to 100mg/kg) were given to four animals during MTD and same animals received three additional doses at 100mg/kg during DRF. Very good tolerability and safety were reported in animals. ALD2510 half-life and exposure were found consistent with that of humanized IgG1 in cynomolgus. Strong TREG depletion was monitored in the blood in all animals with, importantly, no drop was observed in CD4+ or CD8+ T-cells, confirming ALD2510 capacity to selectively target TREGS while sparing TCONV. Overall, ALD2510 demonstrated excellent potency, manufacturability and stability during the 1st phase of preclinical development. Very good tolerability and safety profile together with satisfying PKPD data were reported during exploratory MTD/DRF study in cynomolgus monkeys. Noteworthy, strong TREG depletion was confirmed while CD4+ or CD8+ T-cells were not impacted, confirming ALD2510 selectivity for TREGS while sparing TCONV. This makes ALD2510 a promising candidate for the treatment of solid tumors, in particular those where the presence of TREGS in the TME is associated with worse prognosis and/or resistance to CPI.
Citation Format: Jemila Houacine, Riad Abes, Anne Marie-Cardine, Aude Le Roy, Bettina Serbin, Lucie Robert, Jérôme Giustiniani, Anne-Sophie Chrétien, Stéphane Fattori, Laurent Gorvel, Armand Bensussan, Daniel Olive, Arnaud Foussat. Preclinical development of ALD2510, a Next-Gen Fc-enhanced, TREG-selective and IL-2-sparing anti-CD25 antibody for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 710.