Abstract 752P
Background
Coupling CEA (CEACAM5) on tumor cells and CD3 on T-cells by CEAxCD3 bispecific antibodies activates the latter to destroy CEA-positive cancer cells. Clinical activity is, however, limited, in part by insufficient T-cell activation, dose-limiting toxicities or immunogenicity. Combination with CEA-targeted CD28-costimulation shall increase activity and, when sequentially given, reduce the risk of cytokine release syndrome. We present here preclinical data for the combination of NILK-2301 ± NILK-3301.
Methods
Antibodies were generated using LCB’s fully human κλ body platform based on a common heavy chain and on one κ and one λ light chain, determining specificity and affinity. Non-CEA-targeted CD28-costimulation and superagonism were excluded using T-cell proliferation and activation assays. T-cell dependent cytotoxicity (TDCC) was assessed using colorectal (3), lung (2), and gastric (2) cancer lines with human peripheral blood mononuclear cells (PBMC) in vitro and with a xenograft NOG/human PMBC model in vivo.
Results
NILK-3301 is not superagonistic and activates T-cells only in the presence of CEA-expressing target cells and primary T-cell stimulation. In vitro, NILK-2301 induces dose dependent killing of CEA-positive cell lines. Combination of NILK-2301 (1nM) + NILK-3301 vs. NILK-2301 alone (10nM) induces 3-8-fold increased TDCC including CEA-low expressing lines (e.g., HT-29 [40% vs. 5%] or KATO-III [65% vs. 28%]), increased CD25-expression (CD4+ [75% vs. 5%], CD8+ [85% vs. 40%]), and T-cell proliferation (CD4+ [70% vs. 5%], CD8+ [65% vs. 40%]). Using a two-dose functional assay, sequential vs. simultaneous NILK-2301/NILK-3301 dosing conveys equal activity at reduced IL-6, TNFα, IFNγ, and IL-2 release. In vivo, NILK-2301 (10 mg/kg IV, BIW) decreases tumor progression. Simultaneous or sequential (d+2 or d+4) combo treatment with NILK-3301 induces markedly improved activity and tumor regression in 8/8, 8/8, and 6/8 mice.
Conclusions
NILK-2301 is active as single agent. NILK-2301 + NILK-3301 combination treatment significantly increases activity already at low NILK-2301 doses with reduced cytokine release when given sequentially. IND-filing for NILK-2301 is expected in Q4/2022.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
LamKap Bio.
Funding
LamKap Bio.
Disclosure
A. Seckinger: Financial Interests, Personal, Leadership Role: LamKap Bio Group; Financial Interests, Institutional, Stocks/Shares: LamKap Bio Group. S. Majocchi: Financial Interests, Personal, Full or part-time Employment: Light Chain Bioscience-Novimmune SA. V. Moine: Financial Interests, Personal, Full or part-time Employment: Light Chain Bioscience-Novimmune SA. L. Nouveau: Financial Interests, Personal, Full or part-time Employment: Light Chain Bioscience-Novimmune SA. B. Daubeuf: Financial Interests, Personal, Full or part-time Employment: Light Chain Bioscience-Novimmune SA. V. Buatois: Financial Interests, Personal, Full or part-time Employment: Light Chain Bioscience-Novimmune SA. F. Gueneau: Financial Interests, Personal, Full or part-time Employment: Light Chain Bioscience-Novimmune SA. U. Ravn: Financial Interests, Personal, Full or part-time Employment: Light Chain Bioscience-Novimmune SA. K. Masternak: Financial Interests, Personal, Leadership Role: Light Chain Bioscience-Novimmune SA. Y. Poitevin: Financial Interests, Personal, Full or part-time Employment: Light Chain Bioscience-Novimmune SA. G. Magistrelli: Financial Interests, Personal, Full or part-time Employment: Light Chain Bioscience-Novimmune SA. P. Malinge: Financial Interests, Personal, Full or part-time Employment: Light Chain Bioscience-Novimmune SA. L. Shang: Financial Interests, Personal, Leadership Role: Light Chain Bioscience-Novimmune SA. N. Fischer: Financial Interests, Personal, Leadership Role: Light Chain Bioscience-Novimmune SA; Financial Interests, Personal and Institutional, Stocks/Shares: Light Chain Bioscience-Novimmune SA. K. Strein: Financial Interests, Personal and Institutional, Member of the Board of Directors: LamKap Bio Group; Financial Interests, Personal and Institutional, Stocks/Shares: LamKap Bio Group; Financial Interests, Institutional, Member of the Board of Directors: Light Chain Bioscience-Novimmune SA. W.G. Ferlin: Financial Interests, Personal, Leadership Role: Light Chain Bioscience-Novimmune SA; Financial Interests, Personal and Institutional, Stocks/Shares: Light Chain Bioscience-Novimmune SA. D. Hose: Financial Interests, Personal, Leadership Role: LamKap Bio Group; Financial Interests, Personal and Institutional, Stocks/Shares: LamKap Bio Group.