Immutep and Monash University Announce First Publication Detailing How Human LAG-3 Binds to MHC Class II
Immutep (NASDAQ: IMMP) and Monash University have published groundbreaking research in Science Immunology, revealing the first crystal structure of a human LAG-3/HLA-II complex. The study details how human lymphocyte activation gene 3 (LAG-3) binds to its main ligand MHC Class II, providing important insights for developing blocking LAG-3 therapeutics.
The research supports eftilagimod alfa's (efti) mechanism of action through preferential binding to MHC Class II molecules on antigen-presenting cells. The findings, conducted under Professor Jamie Rossjohn at Monash University's Biomedicine Discovery Institute, demonstrate how LAG-3 engages two HLA-II molecules with a distinct 38° offset angle, advancing understanding of the LAG-3 immune control mechanism.
Immutep (NASDAQ: IMMP) e l'Università di Monash hanno pubblicato ricerche groundbreaking su Science Immunology, rivelando la prima struttura cristallina di un complesso LAG-3/HLA-II umano. Lo studio dettaglia come il gene di attivazione dei linfociti umani 3 (LAG-3) si leghi al suo principale ligando, le molecole MHC Classe II, fornendo importanti dettagli per lo sviluppo di terapie bloccanti per LAG-3.
La ricerca supporta il meccanismo d'azione dell'eftilagimod alfa (efti) attraverso il legame preferenziale con le molecole MHC Classe II sulle cellule presentanti l'antigene. I risultati, condotti sotto la direzione del Professor Jamie Rossjohn presso il Biomedicine Discovery Institute dell'Università di Monash, dimostrano come LAG-3 interagisca con due molecole HLA-II con un angolo di offset distinto di 38°, avanzando la comprensione del meccanismo di controllo immunitario di LAG-3.
Immutep (NASDAQ: IMMP) y la Universidad de Monash han publicado investigaciones pioneras en Science Immunology, revelando la primera estructura cristalina de un complejo LAG-3/HLA-II humano. El estudio detalla cómo el gen de activación de linfocitos humanos 3 (LAG-3) se une a su principal ligando, las moléculas MHC Clase II, proporcionando información importante para el desarrollo de terapias bloqueadoras de LAG-3.
La investigación apoya el mecanismo de acción del eftilagimod alfa (efti) a través de la unión preferencial a las moléculas MHC Clase II en las células presentadoras de antígenos. Los hallazgos, realizados bajo la dirección del Profesor Jamie Rossjohn en el Biomedicine Discovery Institute de la Universidad de Monash, demuestran cómo LAG-3 se compromete con dos moléculas HLA-II con un ángulo de desplazamiento distinto de 38°, avanzando en la comprensión del mecanismo de control inmune de LAG-3.
Immutep (NASDAQ: IMMP)와 모나시대학교는 Science Immunology에 획기적인 연구 결과를 발표하여 인간 LAG-3/HLA-II 복합체의 첫 번째 결정 구조를 밝혀냈습니다. 이 연구는 인간 림프구 활성화 유전자 3(LAG-3)가 주요 리간드인 MHC 클래스 II에 어떻게 결합하는지를 상세히 설명하고 있으며, LAG-3 치료제를 개발하는 데 중요한 통찰력을 제공합니다.
이 연구는 항원 제시 세포의 MHC 클래스 II 분자에 대한 선택적 결합을 통해 eftilagimod alfa(efti)의 작용 메커니즘을 지원합니다. 모나시대학교 생명 의학 발견 연구소에서 Jamie Rossjohn 교수의 지도 아래 수행된 이 연구 결과는 LAG-3가 두 개의 HLA-II 분자와 38°의 독특한 오프셋 각도로 결합하는 방식으로 LAG-3 면역 조절 메커니즘에 대한 이해를 심화시키고 있습니다.
Immutep (NASDAQ: IMMP) et l'Université de Monash ont publié des recherches révolutionnaires dans Science Immunology, révélant la première structure cristalline d'un complexe LAG-3/HLA-II humain. L'étude détaille comment le gène d'activation des lymphocytes humains 3 (LAG-3) se lie à son principal ligand, les molécules MHC classe II, fournissant des informations importantes pour le développement de thérapies bloquantes pour LAG-3.
La recherche soutient le mécanisme d'action de l'eftilagimod alfa (efti) en se liant de manière préférentielle aux molécules MHC classe II sur les cellules présentatrices d'antigènes. Les résultats, réalisés sous la direction du professeur Jamie Rossjohn à l'Institut de découverte biomédicale de l'Université de Monash, montrent comment LAG-3 interagit avec deux molécules HLA-II sous un angle de décalage distinct de 38°, faisant progresser la compréhension du mécanisme de contrôle immunitaire de LAG-3.
Immutep (NASDAQ: IMMP) und die Monash Universität haben bahnbrechende Forschungen in Science Immunology veröffentlicht, die die erste Kristallstruktur eines menschlichen LAG-3/HLA-II-Komplexes enthüllen. Die Studie beschreibt, wie das menschliche Lymphozyten-Aktivierungsgene 3 (LAG-3) an sein wichtigstes Ligand MHC-Klasse-II bindet, was wichtige Einblicke für die Entwicklung von LAG-3-blockierenden Therapeutika bietet.
Die Forschung unterstützt den Wirkmechanismus von eftilagimod alfa (efti) durch die bevorzugte Bindung an MHC-Klasse-II-Moleküle auf antigenpräsentierenden Zellen. Die Ergebnisse, die unter der Leitung von Professor Jamie Rossjohn am Biomedicine Discovery Institute der Monash Universität durchgeführt wurden, zeigen, wie LAG-3 mit zwei HLA-II-Molekülen in einem deutlichen Offsetwinkel von 38° interagiert, was das Verständnis des LAG-3-Immunkontrollmechanismus vorantreibt.
- First-ever resolution of human LAG-3/HLA-II complex crystal structure
- Findings support development of company's anti-LAG-3 small molecule program
- Research validates eftilagimod alfa's mechanism of action
- None.
Insights
- Findings published in Science Immunology resolve how human LAG-3 binds to its main ligand providing a better foundation for development of blocking LAG-3 therapeutics, including Immutep’s anti-LAG-3 small molecule program
- Data also supports eftilagimod alfa’s (efti) preferential binding to a subset of MHC Class II molecules on antigen-presenting cells leading to their activation
SYDNEY, AUSTRALIA, Dec. 16, 2024 (GLOBE NEWSWIRE) -- Immutep Limited (ASX: IMM; NASDAQ: IMMP) ("Immutep” or “the Company”), a clinical-stage biotechnology company developing novel LAG-3 immunotherapies for cancer and autoimmune disease, today announces new findings published in Science Immunology that resolve how human lymphocyte activation gene 3 (LAG-3) binds to its main ligand MHC Class II (MHC-II), also known as HLA Class II (HLA-II) in humans. The publication is the first to show the crystal structure of a human LAG-3/HLA-II complex and provides a better foundation for development of blocking LAG-3 therapeutics, including Immutep’s anti-LAG-3 small molecule program.
Under the oversight of Professor Jamie Rossjohn FAA FRS, at Monash University’s Biomedicine Discovery Institute (BDI), and in collaboration with Immutep, this breakthrough is an exemplar of the importance of industry-academia alliances. The LAG-3 immune control mechanism is the exclusive focus of Immutep across both cancer and autoimmunity and a clinically validated target of deep interest throughout the academic, medical, and industry sectors.
Dr. Jan Petersen, first author of the study, said: “The way the PD-1 and CTLA-4 immune checkpoint molecules bind to their respective ligands has been resolved for many years. However, the resolution of the interface between another important checkpoint molecule, LAG-3, and its main ligands, HLA-II molecules, has remained elusive. Solved using data collected at the Australian Synchrotron, a structure of a LAG-3/HLA-II complex provides a structural foundation to harness rationally for future development of antibodies and small molecule therapeutics designed to block LAG-3 activity.”
Dr. Frédéric Triebel, Immutep’s CSO, added: “It is thrilling to be able to see and analyze the interactions taking place at the interface between the soluble homodimeric LAG-3 protein and its main ligand. We now better understand how efti uniquely acts as an MHC-II agonist by preferentially binding to a subset of MHC-II molecules clustered in lipid raft microdomains on the surface of antigen-presenting cells. These findings add to the strong foundation of our work with Professor Rossjohn and his team to develop a deeper understanding of the structure and function of the LAG-3 immune control mechanism, particularly as it relates to our anti-LAG-3 small molecule program.”
The Crystal Structure of the Human LAG-3–HLA-DR1–Peptide Complex publication details how LAG-3 engages two HLA-II molecules (see Figure 1). The data in the publication supports efti’s (soluble LAG-3) preferential binding to a subset of MHC-II molecules on antigen-presenting cells leading to their activation.
Figure 1: Human LAG-3 homodimer (with domains D1, D2, D3 and D4) binding to two separate HLA-II (MHC-II) molecules on the surface of an antigen-presenting cell (APC), imposing a distinct 38° offset angle. This figure has been modified from the original Figure 1c of Petersen et al to aid visualisation.
About the Monash Biomedicine Discovery Institute
Committed to making the discoveries that will relieve the future burden of disease, the Monash Biomedicine Discovery Institute (BDI) at Monash University brings together more than 120 internationally-renowned research teams. Spanning seven discovery programs across Cancer, Cardiovascular Disease, Development and Stem Cells, Infection, Immunity, Metabolism, Diabetes and Obesity, and Neuroscience, Monash BDI is one of the largest biomedical research institutes in Australia. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.
About Immutep
Immutep is a clinical-stage biotechnology company developing novel LAG-3 immunotherapy for cancer and autoimmune disease. We are pioneers in the understanding and advancement of therapeutics related to Lymphocyte Activation Gene-3 (LAG-3), and our diversified product portfolio harnesses its unique ability to stimulate or suppress the immune response. Immutep is dedicated to leveraging its expertise to bring innovative treatment options to patients in need and to maximise value for shareholders. For more information, please visit www.immutep.com.
Australian Investors/Media:
Catherine Strong, Sodali & Co
+61 (0)406 759 268; catherine.strong@sodali.com
U.S. Media:
Chris Basta, VP, Investor Relations and Corporate Communications
+1 (631) 318 4000; chris.basta@immutep.com
ABN: 90 009 237 889
FAQ
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