RT Journal Article
SR Electronic
T1 1210 A human bispecific antibody targeting LAG-3 and PD-1 (INCA32459) potently activates exhausted T cells
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP A1255
OP A1255
DO 10.1136/jitc-2022-SITC2022.1210
VO 10
IS Suppl 2
A1 Stewart, Shaun
A1 Fransen, Floris
A1 Harvey, Shane
A1 Mortensen, Franziska
A1 Stam, Anita
A1 Awdew, Rahel
A1 Mondal, Arpita
A1 Stevens, Christina
A1 Rovers, Eric
A1 Engels, Steef
A1 Rentrop-Boeijen, Melissa
A1 Hendriks, Linda
A1 Dieren, Brenda van
A1 Buonpane, Rebecca
A1 Visser, Therese
A1 Schellen, Pepijn
A1 Kulkarni, Ashwini
A1 Rios-Doria, Jonathan
A1 Zhou, Jing
A1 Tacken, Paul
A1 Lu, Lu
A1 Zande, Vanessa Zondag-van der
A1 Huang, Cheng-Yen
A1 Blanken-Smit, Renate den
A1 Kruif, John de
A1 Klooster, Rinse
A1 Plyte, Simon
A1 Nastri, Horacio
A1 Mayes, Patrick
YR 2022
UL http://jitc.bmj.com/content/10/Suppl_2/A1255.abstract
AB Background Exhausted T cells are characterized by the expression of negative immune regulatory receptors, including programmed death protein-1 (PD-1) and lymphocyte-activation gene 3 (LAG-3), which inhibit the proliferation and function of T cells and limit antitumor immunity. We describe the generation and characterization of INCA32459, a human IgG1 Fc-silenced bispecific antibody that simultaneously binds to PD-1 and LAG-3 and reverts their inhibitory function.Methods INCA32459 was generated using the Merus common light chain Biclonics® platform. LAG-3 and PD-1 Fab panels were generated through immunization of Merus MeMo® mice, and large panels of Biclonics® libraries were screened before optimizing lead candidate molecules.Results INCA32459 binds with high affinity to both human (KD=0.39 nM) and cynomolgus monkey (KD=0.44 nM) PD-1, and human (KD=1.15 nM) and cynomolgus monkey (KD=0.20 nM) LAG-3, as measured by surface plasmon resonance. The monovalent PD-1 arm of INCA32459 blocks PD-1 with similar potency as a bivalent PD-1 antibody (nivolumab analog) in a PD-1/PD-L1 reporter assay. In a loss-of-function reporter assay where luciferase expression increases upon blockade of both LAG-3 and PD-1, INCA32459 significantly induced luciferase expression to a greater extent than either PD-1 (nivolumab analog) or LAG-3 (relatlimab analog) single agent antibody controls, and greater than PD-1 (nivolumab) and LAG-3 (relatlimab) analog antibodies combined. In 2 human primary immune cell assays, a T-cell exhaustion model using chronically SEB-stimulated peripheral blood mononuclear cells (PBMCs), and an antigen recall assay using CEFT MHCII peptide pool-stimulated PBMCs, INCA32459 treatment resulted in higher interleukin-2 and interferon-y induction, respectively, compared with PD-1 (nivolumab analog) and LAG-3 (relatlimab analog) antibodies combined. In a human MDA-MB-231 breast tumor model in CD34+ humanized NSG mice, INCA32459 treatment decreased tumor growth compared with a combination of PD-1 (pembrolizumab) and LAG-3 (relatlimab analog) antibodies. Pharmacodynamic analysis in mice demonstrated a dose-dependent increase in receptor occupancy at 1 and 10 mg/kg. Pharmacokinetic characterization of INCA32459 in cynomolgus monkeys after a single IV infusion at 3 and 30 mg/kg demonstrated an average clearance, steady-state volume of distribution, and mean residence time of 0.515 mL/h/kg, 74.1 mL/kg, and 144 h, respectively.Conclusions We have developed INCA32459, a potent dual inhibitor of PD-1 and LAG-3 in preclinical models, which induces activation of exhausted T cells to a greater extent than a combination of bivalent monospecific antibodies targeting PD-1 (nivolumab analog) and LAG-3 (relatlimab analog). These data support the clinical evaluation of INCA32459, and a phase 1 study in cancer patients is underway.