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The engineered CD80 variant fusion therapeutic davoceticept combines checkpoint antagonism with conditional CD28 costimulation for anti-tumor immunity.

<div class='caption-title'>ALPN-202, a variant CD80 IgV domain Fc fusion, binds human PD-L1, CD28, and CTLA-4 with high affinity.</div>
<div class='caption-title'>CD28 costimulation by ALPN-202 requires TCR activation and co-binding to PD-L1.</div>
<div class='caption-title'>Crystal Structure of ALPN-202 CD80 vIgD complexed with the wild type PD-L1 ECD.</div>
Maurer MF, Lewis KE, Kuijper JL, Ardourel D, Gudgeon CJ, Chandrasekaran S, Mudri SL, Kleist KN, Navas C, Wolfson MF, Rixon MW, Swanson R, Dillon SR, Levin SD, Kimbung YR, Akutsu M, Logan DT, Walse B, Swiderek KM, Peng SL
OpenAccess logo Nat Commun 13 1790 (2022)
Cited: 8 times
EuropePMC logo PMID: 35379805

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.

Articles - 7tps mentioned but not cited (2)

  1. The engineered CD80 variant fusion therapeutic davoceticept combines checkpoint antagonism with conditional CD28 costimulation for anti-tumor immunity. Maurer MF, Lewis KE, Kuijper JL, Ardourel D, Gudgeon CJ, Chandrasekaran S, Mudri SL, Kleist KN, Navas C, Wolfson MF, Rixon MW, Swanson R, Dillon SR, Levin SD, Kimbung YR, Akutsu M, Logan DT, Walse B, Swiderek KM, Peng SL. Nat Commun 13 1790 (2022)
  2. Identification, binding, and structural characterization of single domain anti-PD-L1 antibodies inhibitory of immune regulatory proteins PD-1 and CD80. Kang-Pettinger T, Walker K, Brown R, Cowan R, Wright H, Baravalle R, Waters LC, Muskett FW, Bowler MW, Sawmynaden K, Coombs PJ, Carr MD, Hall G. J Biol Chem 299 102769 (2023)


Reviews citing this publication (2)

  1. Immune checkpoint inhibitor-associated cardiovascular toxicities: A review. Liu G, Chen T, Zhang X, Hu B, Shi H. Heliyon 10 e25747 (2024)
  2. CD80-Fc fusion protein as a potential cancer immunotherapy strategy. Wang S, Hu P, Fan J, Zou J, Hong W, Huang X, Pan D, Chen H, Zhu YZ, Ye L. Antib Ther 7 28-36 (2024)

Articles citing this publication (4)

  1. Letter Structural and biological characterization of pAC65, a macrocyclic peptide that blocks PD-L1 with equivalent potency to the FDA-approved antibodies. Rodriguez I, Kocik-Krol J, Skalniak L, Musielak B, Wisniewska A, Ciesiołkiewicz A, Berlicki Ł, Plewka J, Grudnik P, Stec M, Siedlar M, Holak TA, Magiera-Mularz K. Mol Cancer 22 150 (2023)
  2. Society for Immunotherapy of Cancer (SITC) recommendations on intratumoral immunotherapy clinical trials (IICT): from premalignant to metastatic disease. Luke JJ, Davar D, Andtbacka RH, Bhardwaj N, Brody JD, Chesney J, Coffin R, de Baere T, de Gruijl TD, Fury M, Goldmacher G, Harrington KJ, Kaufman H, Kelly CM, Khilnani AD, Liu K, Loi S, Long GV, Melero I, Middleton M, Neyns B, Pinato DJ, Sheth RA, Solomon SB, Szapary P, Marabelle A. J Immunother Cancer 12 e008378 (2024)
  3. A combination of a TLR7/8 agonist and an epigenetic inhibitor suppresses triple-negative breast cancer through triggering anti-tumor immune. Jiang Z, Cai G, Liu H, Liu L, Huang R, Nie X, Gui R, Li J, Ma J, Cao K, Luo Y. J Nanobiotechnology 22 296 (2024)
  4. Phase I studies of davoceticept (ALPN-202), a PD-L1-dependent CD28 co-stimulator and dual PD-L1/CTLA-4 inhibitor, as monotherapy and in combination with pembrolizumab in advanced solid tumors (NEON-1 and NEON-2). Davar D, Cavalcante L, Lakhani N, Moser J, Millward M, McKean M, Voskoboynik M, Sanborn RE, Grewal JS, Narayan A, Patnaik A, Gainor JF, Sznol M, Enstrom A, Blanchfield L, LeBlanc H, Thomas H, Chisamore MJ, Peng SL, Naumovski A. J Immunother Cancer 12 e009474 (2024)


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