Abl501, Pd-L1 X Lag-3, A Bispecific Antibody Promotes Enhanced Human T Cell Activation Through Targeting Simultaneously Two Immune Checkpoint Inhibitors, Lag-3 And Pd-L1.

Abstract PD-(L)1 blockade has demonstrated the remarkable success for cancer treatment, but significant unmet needs remain to fully achieve clinical benefit for PD-(L)1 resistant/refractory patients. Recent studies suggest that expression of Lymphocyte Activation Gene 3 (LAG-3) on exhausted T cells may be a key factor responsible for resistance to therapies targeting PD-(L)1. LAG-3 is mainly expressed on the activated T cells where it also functions as a negative regulator of T cell function. Despite enhanced antitumor efficacy in preclinical studies, combinational effect of anti-LAG-3 and PD-(L)1-targeted therapeutics has been modest unless patients were stratified with LAG-3 high group. To overcome limitations of current LAG-3-targeting antibodies, ABL501, a LAG-3/PD-L1 bispecific antibody, is generated by the genetic fusion of scFv-PD-L1 to the LAG-3 with an engineered IgG4 isotype so that PD-1/PD-L1 blockade can be made more often in the LAG-3 high tumor microenvironment. Functional evaluation data by using various cell-based assays and patient-derived lung cancer organoids indicate that ABL501 retains full checkpoint blockade activity of both PD-1/PD-L1 and LAG-3/MHCII signaling axis. Furthermore, ABL501 shows a co-blockade of PD-(L)1 and LAG-3 leading to a synergistic increase of T cell activation higher than the enhancements induced by combination of anti-PD-L1 and LAG-3. Antitumor effects of ABL501 were demonstrated in studies with humanized Balb/c-hPD-1/hLAG-3 mice subcutaneously inoculated with CT26-hPD-L1 tumor cells. In a preclinical study using a humanized mouse model, ABL501 shows dose-dependent tumor growth inhibition with maximum effect at 10 mg/kg which was superior to anti-PD-L1 alone. The safety of ABL501 in a pivotal GLP study was evaluated in cynomolgus monkeys by dosing twice weekly for a total of 8 administrations over a 28-day period. Reversibility of the findings was evaluated following a 56-day recovery period. The toxicokinetics (TK) and immunology of ABL501 were also determined. ABL501 was well-tolerated and the no observed adverse effect level (NOAEL) was considered to be 200 mg/kg/dose. Together with safety profile in the toxicology study, the preclinical studies support that ABL501 effectively suppressed tumor growth through activation of immune cells by releasing immune suppressive environments. This alternative therapeutic strategy may have a potential to overcome limitations of the current immune-oncology therapy for further clinical evaluation. Citation Format: Eunyoung Park, Hyunejoo Kim, Eunsil Sung, Uijung Jung, Youngeun Hong, Hanbyul Lee, Minkyung Ko, Yoon Park, Chan Kwon Park, Seung Joon Kim, Jongman Yoo, Kyung Jin Lee, Jihyo Kim, Bo Eun Lee, Jonghwa Won, Jaeho Jung. ABL501, PD-L1 x LAG-3, a bispecific antibody promotes enhanced human T cell activation through targeting simultaneously two immune checkpoint inhibitors, LAG-3 and PD-L1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1633.