To improve ICB by enhancing CD28 costimulation, Maurer et al. created ALPN-202 (davoceticept), a dimer of an inert Ig Fc fused to a human CD80 IgV domain variant that was derived by directed evolution, had improved affinity for and could simultaneously bind human PD-L1 and CD28, and retained strong binding to CTLA-4. The ALPN-202 CD80 IgV/PD-L1 ECD crystal structure was solved. ALPN-202 induced PD-L1-dependent CD28 costimulation of T cells in vitro – enabled by PD-L1+ M2 macrophages and inhibited by CD28 or PD-L1 blockade – and enhanced T cell and antitumor activity in mouse models, particularly using human PD-L1+ tumors.
Contributed by Paula Hochman
ABSTRACT: Despite the recent clinical success of T cell checkpoint inhibition targeting the CTLA-4 and PD-1 pathways, many patients either fail to achieve objective responses or they develop resistance to therapy. In some cases, poor responses to checkpoint blockade have been linked to suboptimal CD28 costimulation and the inability to generate and maintain a productive adaptive anti-tumor immune response. To address this, here we utilize directed evolution to engineer a CD80 IgV domain with increased PD-L1 affinity and fuse this to an immunoglobulin Fc domain, creating a therapeutic (ALPN-202, davoceticept) capable of providing CD28 costimulation in a PD-L1-dependent fashion while also antagonizing PD-1 - PD-L1 and CTLA-4-CD80/CD86 interactions. We demonstrate that by combining CD28 costimulation and dual checkpoint inhibition, ALPN-202 enhances T cell activation and anti-tumor efficacy in cell-based assays and mouse tumor models more potently than checkpoint blockade alone and thus has the potential to generate potent, clinically meaningful anti-tumor immunity in humans.
Author Info: (1) Alpine Immune Sciences, Inc., Seattle, WA, USA. Mark.Maurer@AlpineImmuneSciences.com. (2) Alpine Immune Sciences, Inc., Seattle, WA, USA. (3) Alpine Immune Sciences, Inc., Seat
Author Info: (1) Alpine Immune Sciences, Inc., Seattle, WA, USA. Mark.Maurer@AlpineImmuneSciences.com. (2) Alpine Immune Sciences, Inc., Seattle, WA, USA. (3) Alpine Immune Sciences, Inc., Seattle, WA, USA. (4) Alpine Immune Sciences, Inc., Seattle, WA, USA. (5) Alpine Immune Sciences, Inc., Seattle, WA, USA. (6) Alpine Immune Sciences, Inc., Seattle, WA, USA. Notch Therapeutics, Inc., Seattle, WA, USA. (7) Alpine Immune Sciences, Inc., Seattle, WA, USA. (8) Alpine Immune Sciences, Inc., Seattle, WA, USA. (9) Alpine Immune Sciences, Inc., Seattle, WA, USA. Lyell Immunopharma, Inc., Seattle, WA, USA. (10) Alpine Immune Sciences, Inc., Seattle, WA, USA. (11) Alpine Immune Sciences, Inc., Seattle, WA, USA. (12) Alpine Immune Sciences, Inc., Seattle, WA, USA. Neoleukin Therapeutics, Inc., Seattle, WA, USA. (13) Alpine Immune Sciences, Inc., Seattle, WA, USA. (14) Alpine Immune Sciences, Inc., Seattle, WA, USA. Parvus Therapeutics, Inc., South San Francisco, CA, USA. (15) SARomics Biostructures AB, Medicon Villiage, Lund, Sweden. (16) SARomics Biostructures AB, Medicon Villiage, Lund, Sweden. Department of Chemistry, Keio University, Yokohama, Japan. (17) SARomics Biostructures AB, Medicon Villiage, Lund, Sweden. (18) SARomics Biostructures AB, Medicon Villiage, Lund, Sweden. (19) Alpine Immune Sciences, Inc., Seattle, WA, USA. Mozart Therapeutics, Inc., Seattle, WA, USA. (20) Alpine Immune Sciences, Inc., Seattle, WA, USA.
