Project Overview

PD-1 acts as a critical checkpoint that prevents T cells from becoming overactive, but current therapies that target this pathway have shown limited efficacy. Recent research by this team revealed that PD-1 functions most effectively when two PD-1 proteins dimerize through their transmembrane domains — and that this dimerization is directly linked to T cell inhibition and immune tolerance. This project aims to develop novel monoclonal antibodies that trigger PD-1 dimerization by targeting the membrane-proximal external region (MPER) of PD-1, close to the cell surface. By inducing this pairing more deliberately, the antibodies are designed to more effectively calm the immune system, with potential applications across a range of autoimmune conditions.

Impact & Innovation

A new way to quiet an overactive immune system.

 

By deliberately inducing PD-1 dimerization — a newly discovered mechanism of T cell inhibition — this project opens a fundamentally different path to treating autoimmune disease.

  • Introduces a previously unexploited mechanism for immune tolerance, distinct from existing PD-1–targeting approaches
  • Has potential application across multiple autoimmune conditions including rheumatoid arthritis, lupus, and type 1 diabetes
  • Advances the Consortium’s From Mechanistic Insight to Translation pillar, moving a novel molecular discovery toward a patentable biologic with a defined preclinical development pathway
Research Approach

A framework designed for discovery

This project integrates structural biology, antibody engineering, and in vivo immunology to develop and validate PD-1 agonist biologics that work through a dimerization-based mechanism. The study moves from molecular design to functional testing, with the goal of producing candidates ready for preclinical development.

Structure-guided design and development of monoclonal antibodies targeting the MPER of PD-1, in vitro binding and functional assays to confirm dimerization and T cell inhibition, and murine autoimmune models to evaluate therapeutic efficacy and tolerability.

Structural data on PD-1 transmembrane and MPER domains, in vitro cell-based assays measuring T cell activation and PD-1 dimerization, and murine models of autoimmune disease to assess in vivo immune suppression.

Validation of PD-1 dimerization as a therapeutically actionable mechanism, with a focus on identifying lead antibody candidates that demonstrate robust T cell suppression. Successful candidates would advance toward preclinical development and, ultimately, first-in-human trials for autoimmune diseases such as rheumatoid arthritis, lupus, and type 1 diabetes.

Investigators & Institutions

Powering the science

Principal Investigators

Xiangpeng Kong, PhD, Colton Consortium Member

Professor, Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, NYU Langone Health

Elliot A. Philips, MD, PhD, Colton Consortium Member

Rheumatology Fellow; Breidenbach Scholar, Judith and Stewart Colton Center for Autoimmunity, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health

Jun Wang, PhD, Colton Consortium Member

Associate Professor, Department of Pathology, NYU Grossman School of Medicine / NYU Langone Health

Research Outputs

From insight to impact

Publications

Proximity between LAG-3 and the T cell receptor guides suppression of T cell activation and autoimmunity

Cell
Silberstein, JL; Du, J; Chan, K; Frank, JA; Mathews, II; Kim, YB; You, J; Lu, Q; Liu, J; Philips, EA; Liu, P; Rao, E; Fernandez, D; Rodriguez, GE; Kong, X; Wang, J; Cochran, JR July 2025
Animal ModelsBiological & MechanisticCytokine SignalingExperimental Platforms & ModelsImmune ToleranceIn Vitro ModelsPrecision MedicineT Cell BiologyTherapeutic DevelopmentTranslational & ClinicalOtherNew York University

Skin immune-mesenchymal interplay within tertiary lymphoid structures promotes autoimmune pathogenesis in hidradenitis suppurativa

Immunity
Yu, WW; Barrett, JNP; Tong, J; Lin, MJ; Marohn, M; Devlin, JC; Herrera, A; Remark, J; Levine, J; Liu, PK; Fang, V; Zellmer, AM; Oldridge, DA; Wherry, EJ; Lin, JR; Chen, JY; Sorger, P; Santagata, S; Krueger, JG; Ruggles, KV; Wang, F; Su, C; Koralov, SB; Wang, J; Chiu, ES; Lu, CP December 2024
Adaptive ImmunityB Cell BiologyBioinformaticsBiological & MechanisticCytokine SignalingData-Driven & QuantitativeExperimental Platforms & ModelsImmune ProfilingInnate ImmunitySingle Cell TechnologiesSpatial BiologyT Cell BiologyDermatologic DiseasesOtherUniversity of Pennsylvania

Structural insights reveal interplay between LAG-3 homodimerization, ligand binding, and function

Proceedings of the National Academy of Sciences
Silberstein, JL; Du, J; Chan, K; Frank, JA; Mathews, II; Kim, YB; You, J; Lu, Q; Liu, J; Philips, EA; Liu, P; Rao, E; Fernandez, D; Rodriguez, GE; Kong, X; Wang, J; Cochran, JR March 2024
Animal ModelsBiological & MechanisticBiomarker DiscoveryExperimental Platforms & ModelsImmune ToleranceIn Vitro ModelsT Cell BiologyTherapeutic DevelopmentTranslational & ClinicalOtherOverlap SyndromesNew York University

Transmembrane domain–driven PD-1 dimers mediate T cell inhibition

Science Immunology
Philips, EA; Liu, J; Kvalvaag, A; Mørch, AM; Tocheva, AS; Ng, C; Liang, H; Ahearn, IM; Pan, R; Luo, CC; Leithner, A; Qin, Z; Zhou, Y; Garcia-España, A; Mor, A; Littman, DR; Dustin, ML; Wang, J; Kong, X-P March 2024
Animal ModelsBiological & MechanisticExperimental Platforms & ModelsImmune ToleranceIn Vitro ModelsPrecision MedicineT Cell BiologyTherapeutic DevelopmentTranslational & ClinicalOtherNew York University