Slide 1: Rosnilimab, a PD-1 Agonist Antibody that Binds to a Membrane Proximal Epitope
Abstract Number: #1726681 Rosnilimab, a PD-1 Agonist Antibody that Binds to a Membrane Proximal Epitope Leading to Optimized PD-1 Agonistic Signaling Stephen Parmley, Benjamin Szlyk, Richard T. Frank, Matthew Hsu, Polina Brodsky, Yangsu Ren, Cailin Sibley, Paul Lizzul, and Martin Dahl AnaptysBio, In
Slide 2: Checkpoint Receptors Modulate Immune Cells
Checkpoint Receptors Modulate Immune Cells Checkpoint Checkpoint antagonists: Checkpoint receptors agonists: “release the (e.g., PD-1, BTLA) “tap the brakes” brakes” Treat inflammation: Treat cancers: Immune cells Attenuate Unleash immune (e.g., T, B, overactive/persistent response dendritic cells)
Slide 3: Role of PD-1 in Rheumatoid Arthritis (RA)
Role of PD-1 in Rheumatoid Arthritis (RA) • PD-1+ T cells broadly impact multiple clinically validated drivers of Higher Prevalence of PD-1+ T Cells RA pathogenesis2 in RA1 • PD-1high Tph cells are elevated in RA synovium and secrete cytokines Inflamed Tissue PD-1+ T Cell driving autoantibody produc
Slide 4: Rosnilimab (PD-1 agonist, IgG1)
Rosnilimab (PD-1 agonist, IgG1) Antibody Characteristics Dendritic cell • Checkpoint ligands bind to receptors, forming CD80/86 MHC PD-L1 tight synapses to enable clustering and exclusion of large phosphatases resulting in checkpoint agonism1 • Rosnilimab binds to PD-1 at a membrane Fc Receptor prox
Slide 5: Rosnilimab has Dual Mechanisms of Depletion and PD-1 Agonism
Rosnilimab has Dual Mechanisms of Depletion and PD-1 Agonism 5
Slide 6: Rosnilimab Binds to a Membrane Proximal Epitope of PD-1 while Reference 1 Binds a Membrane Distal Epitope
Rosnilimab Binds to a Membrane Proximal Epitope of PD-1 while Reference 1 Binds a Membrane Distal Epitope Epitope mapping using wild-type or mutant human PD-1 Rosnilimab binds to a PD-1 epitope distinct from the PD-L1 binding pocket Cell membrane Rosnilimab epitope Reference 1 epitope PD-1 agonist a
Slide 7: Evaluating PD-1 Agonism Using Primary Immune Cells
Evaluating PD-1 Agonism Using Primary Immune Cells • Objective: Evaluate the contribution of PD-1 membrane proximal binding and FcR engagement to PD-1 agonism, when there are no cells capable of mediating depletion in this assay 7
Slide 8: Greater Potency of Agonism by Membrane Proximal Binding Rosnilimab
Greater Potency of Agonism (Reduced T Cell Proliferation) by Membrane Proximal Binding Rosnilimab T Cell PD-1 Membrane Test Article Proliferation Binding Reduction* Reference 1 Distal ~20% Rosnilimab Proximal ~75% *Compared to isotype control Parmley, et al. Presented at the ECCO meeting, Stockholm,
Slide 9: Evaluating Depletion (ADCC) of PD-1+ T Cells Using Primary Immune Cells
Evaluating Depletion (ADCC) of PD-1+ T Cells Using Primary Immune Cells 16 hour Co-culture • Objective: Evaluate the contribution of PD-1 membrane proximal binding and FcR engagement to depletion of PD-1+ T cells 9
Slide 10: Greater Potency in Depletion of PD-1+ T Cells by Membrane Proximal Binding Rosnilimab
Greater Potency in Depletion of PD-1+ T Cells by Membrane Proximal Binding Rosnilimab PD-1 Membrane PD-1+ T Cell Test Article Binding Reduction* Reference 1 Distal ~40% Rosnilimab Proximal ~70% *Compared to isotype control Parmley, et al. Presented at the ECCO meeting, Stockholm, Feb 21-24 2024 10
Slide 11: Rosnilimab's Potent Depletion and Agonism Reduced T Cell Proliferation and Inflammatory Cytokines
Rosnilimab’s Potent Depletion and Agonism Reduced T Cell Proliferation and Inflammatory Cytokines from RA Patient PBMCs Isotype control cells 100 isotype) Isotype control Tcells 100 toisotype) Isotype control T Tcells 100 Inhibition of Tfh/Tph chemokine totoisotype) Depletion of PD-1high T cells 75
Slide 12: PD-1 Agonism By Membrane Proximal Binding Rosnilimab Reduced T Cell Activation Associated Genes
PD-1 Agonism By Membrane Proximal Binding Rosnilimab Reduced T Cell Activation Associated Genes Gene Expression Analysis Monocytes were purified from healthy donor PBMCs, polarized to dendritic cells, and co-cultured with isolated PanT cells in the presence of 30nM PD-1 antibodies or isotype control
Slide 13: Conclusions
Conclusions • Rosnilimab binds to a membrane proximal region of PD-1 while reference 1 binds to a more membrane distal region • Optimization of rosnilimab’s binding characteristics results in more potent agonism and deeper depletion of PD-1 expressing T cells compared to reference 1 • Results were c