Novel Immunomodulatory Proteins Generated Via Directed Evolution of Variant IgSF Domains

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2020 Feb 11

PMID 32038630

Citations 4

Authors

Steven D Levin

Lawrence S Evans

Susan Bort

Erika Rickel

Katherine E Lewis

Rebecca P Wu

Joseph Hoover

Sean MacNeil

David La

Martin F Wolfson

Mark W Rixon

Stacey R Dillon

Michael G Kornacker

Ryan Swanson

Stanford L Peng

Affiliations

Soon will be listed here.

Abstract

Immunoglobulin superfamily member (IgSF) proteins play a significant role in regulating immune responses with surface expression on all immune cell subsets, making the IgSF an attractive family of proteins for therapeutic targeting in human diseases. We have developed a directed evolution platform capable of engineering IgSF domains to increase affinities for cognate ligands and/or introduce binding to non-cognate ligands. Using this scientific platform, ICOSL domains have been derived with enhanced binding to ICOS and with additional high-affinity binding to the non-cognate receptor, CD28. Fc-fusion proteins containing these engineered ICOSL domains significantly attenuate T cell activation and and can inhibit development of inflammatory diseases in mouse models. We also present evidence that engineered ICOSL domains can be formatted to selectively provide costimulatory signals to augment T cell responses. Our scientific platform thus provides a system for developing therapeutic protein candidates with selective biological impact for treatments of a wide array of human disorders including cancer and autoimmune/inflammatory diseases.

Citing Articles

Systemic Administration of Acazicolcept, a Dual CD28 and Inducible T cell Costimulator Inhibitor, Ameliorates Experimental Autoimmune Uveitis.

Wilson L, Lewis K, Evans L, Dillon S, Pepple K Transl Vis Sci Technol. 2023; 12(3):27.

PMID: 36976157 PMC: 10064916. DOI: 10.1167/tvst.12.3.27.

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

Maurer M, Lewis K, Kuijper J, Ardourel D, Gudgeon C, Chandrasekaran S Nat Commun. 2022; 13(1):1790.

PMID: 35379805 PMC: 8980021. DOI: 10.1038/s41467-022-29286-5.

First-in-human study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of ALPN-101, a dual CD28/ICOS antagonist, in healthy adult subjects.

Yang J, Lickliter J, Hillson J, Means G, Sanderson R, Carley K Clin Transl Sci. 2021; 14(4):1314-1326.

PMID: 33503289 PMC: 8301585. DOI: 10.1111/cts.12983.

ICOSL plasmacytoid dendritic cells as inducer of graft-versus-host disease, responsive to a dual ICOS/CD28 antagonist.

Adom D, Dillon S, Yang J, Liu H, Ramadan A, Kushekhar K Sci Transl Med. 2020; 12(564).

PMID: 33028709 PMC: 7811191. DOI: 10.1126/scitranslmed.aay4799.

References

Mease P, Gottlieb A, van der Heijde D, FitzGerald O, Johnsen A, Nys M . Efficacy and safety of abatacept, a T-cell modulator, in a randomised, double-blind, placebo-controlled, phase III study in psoriatic arthritis. Ann Rheum Dis. 2017; 76(9):1550-1558. PMC: 5561378. DOI: 10.1136/annrheumdis-2016-210724. View

Vincenti F, Larsen C, Durrbach A, Wekerle T, Nashan B, Blancho G . Costimulation blockade with belatacept in renal transplantation. N Engl J Med. 2005; 353(8):770-81. DOI: 10.1056/NEJMoa050085. View

Brandt C, Baratin M, Yi E, Kennedy J, Gao Z, Fox B . The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. J Exp Med. 2009; 206(7):1495-503. PMC: 2715080. DOI: 10.1084/jem.20090681. View

Dull T, Zufferey R, Kelly M, Mandel R, Nguyen M, Trono D . A third-generation lentivirus vector with a conditional packaging system. J Virol. 1998; 72(11):8463-71. PMC: 110254. DOI: 10.1128/JVI.72.11.8463-8471.1998. View

Yao S, Zhu Y, Zhu G, Augustine M, Zheng L, Goode D . B7-h2 is a costimulatory ligand for CD28 in human. Immunity. 2011; 34(5):729-40. PMC: 3103603. DOI: 10.1016/j.immuni.2011.03.014. View

Hui E, Cheung J, Zhu J, Su X, Taylor M, Wallweber H . T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science. 2017; 355(6332):1428-1433. PMC: 6286077. DOI: 10.1126/science.aaf1292. View

Yoshinaga S, Whoriskey J, Khare S, Sarmiento U, Guo J, Horan T . T-cell co-stimulation through B7RP-1 and ICOS. Nature. 2000; 402(6763):827-32. DOI: 10.1038/45582. View

Carter P, Presta L, Gorman C, Ridgway J, Henner D, Wong W . Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci U S A. 1992; 89(10):4285-9. PMC: 49066. DOI: 10.1073/pnas.89.10.4285. View

Derer S, Beurskens F, Rosner T, Peipp M, Valerius T . Complement in antibody-based tumor therapy. Crit Rev Immunol. 2014; 34(3):199-214. DOI: 10.1615/critrevimmunol.2014009761. View

10.

Burmeister Y, Lischke T, Dahler A, Mages H, Lam K, Coyle A . ICOS controls the pool size of effector-memory and regulatory T cells. J Immunol. 2008; 180(2):774-82. DOI: 10.4049/jimmunol.180.2.774. View

11.

Chattopadhyay K, Bhatia S, Fiser A, Almo S, Nathenson S . Structural basis of inducible costimulator ligand costimulatory function: determination of the cell surface oligomeric state and functional mapping of the receptor binding site of the protein. J Immunol. 2006; 177(6):3920-9. DOI: 10.4049/jimmunol.177.6.3920. View

12.

Halaby D, Mornon J . The immunoglobulin superfamily: an insight on its tissular, species, and functional diversity. J Mol Evol. 1998; 46(4):389-400. DOI: 10.1007/pl00006318. View

13.

Wekerle T, Grinyo J . Belatacept: from rational design to clinical application. Transpl Int. 2011; 25(2):139-50. DOI: 10.1111/j.1432-2277.2011.01386.x. View

14.

Ochoa M, Minute L, Rodriguez I, Garasa S, Perez-Ruiz E, Inoges S . Antibody-dependent cell cytotoxicity: immunotherapy strategies enhancing effector NK cells. Immunol Cell Biol. 2017; 95(4):347-355. DOI: 10.1038/icb.2017.6. View

15.

Yu X, Abe R, Hodes R . The role of B7-CD28 co-stimulation in tumor rejection. Int Immunol. 1998; 10(6):791-7. DOI: 10.1093/intimm/10.6.791. View

16.

Esensten J, Helou Y, Chopra G, Weiss A, Bluestone J . CD28 Costimulation: From Mechanism to Therapy. Immunity. 2016; 44(5):973-88. PMC: 4932896. DOI: 10.1016/j.immuni.2016.04.020. View

17.

Topalian S, Hodi F, Brahmer J, Gettinger S, Smith D, Mcdermott D . Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012; 366(26):2443-54. PMC: 3544539. DOI: 10.1056/NEJMoa1200690. View

18.

de Felipe P, Martin V, Cortes M, Ryan M, Izquierdo M . Use of the 2A sequence from foot-and-mouth disease virus in the generation of retroviral vectors for gene therapy. Gene Ther. 1999; 6(2):198-208. DOI: 10.1038/sj.gt.3300811. View

19.

Carter L, Carreno B . Cytotoxic T-lymphocyte antigen-4 and programmed death-1 function as negative regulators of lymphocyte activation. Immunol Res. 2003; 28(1):49-59. DOI: 10.1385/IR:28:1:49. View

20.

Wolchok J, Hodi F, Weber J, Allison J, Urba W, Robert C . Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci. 2013; 1291:1-13. PMC: 3910157. DOI: 10.1111/nyas.12180. View