Lymphocyte activation gene-3 (LAG-3) is an immune checkpoint receptor that drives T cell exhaustion and tumor immune evasion. While antibody-based LAG-3 inhibitors have entered clinical practice, their poor tumor penetration, high manufacturing costs, and prolonged half-lives limit dosing flexibility and can lead to extended immune-related toxicities. Potent small molecule LAG-3 inhibitors remain elusive, leaving a major gap in the immuno-oncology landscape. Here, we report the discovery of LAGi-DEL, the first nanomolar small molecule LAG-3 inhibitor, identified through screening a 4.2-billion compound DNA-encoded chemical library (DEL). LAGi-DEL binds directly to LAG-3 with a K_d of 97 nM (SPR) and 271 nM (MST) and disrupts the LAG-3/MHC-II interaction with an EC₅₀ of 138 nM, the highest potency reported for a small molecule against LAG-3. Molecular docking and dynamics simulations reveal that LAGi-DEL induces stabilizing conformational changes within the LAG-3 binding pocket. Functionally, LAGi-DEL restores T cell activation, elevates IFN-γ secretion, and promotes immune-mediated killing in acute myeloid leukemia and lung cancer co-culture models, matching the efficacy of the FDA-approved antibody relatlimab. Pharmacokinetic profiling shows favorable drug-like properties, including high solubility, acceptable permeability, robust metabolic and plasma stability, low cytotoxicity toward normal cells, and negligible hERG and CYP liabilities. These attributes, combined with broad functional activity and unprecedented potency, position LAGi-DEL as a promising scaffold for developing orally available LAG-3 inhibitors and as a blueprint for next-generation immune checkpoint therapeutics.

2024-11-01·BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Design and Biophysical Characterization of Second-Generation cyclic peptide LAG-3 inhibitors for cancer immunotherapy

Article

作者: Zhang, Longfei ; Ali, Yasir ; Calvo-Barreiro, Laura ; Ur Rehman, Ashfaq ; Gabr, Moustafa

Lymphocyte activation gene 3 (LAG-3) is an inhibitory immune checkpoint crucial for suppressing the immune response against cancer. Blocking LAG-3 interactions enables T cells to recover their cytotoxic capabilities and diminishes the immunosuppressive effects of regulatory T cells. A cyclic peptide (Cys-Val-Pro-Met-Thr-Tyr-Arg-Ala-Cys, disulfide bridge: 1-9) was recently reported as a LAG-3 inhibitor. Based on this peptide, we designed 19 derivatives by substituting tyrosine residue to maximize LAG-3 inhibition. Screening via TR-FRET assay identified 8 outperforming derivatives, with cyclic peptides 12 [Tyr6(L-3-CN-Phe)], 13 [Tyr6(L-4-NH₂-Phe)], and 17 [Tyr6(L-3,5-DiF-Phe)] as top candidates. Cyclic peptide 12 exhibited the highest inhibition (IC₅₀ = 4.45 ± 1.36 µM). MST analysis showed cyclic peptides 12 and 13 bound LAG-3 with K_D values of 2.66 ± 2.06 µM and 1.81 ± 1.42 µM, respectively, surpassing the original peptide (9.94 ± 4.13 µM). Docking simulations revealed that cyclic peptide 12 exhibited significantly enhanced binding, with a docking score of -7.236 kcal/mol, outperforming the original peptide (-5.236 kcal/mol) and cyclic peptide 5 (L-4-CN-Phe) (-5.131 kcal/mol). A per-residue decomposition of the interaction energy indicated that the 3-cyano group in cyclic peptide 12 contributes to a more favorable conformation, yielding an interaction energy of -9.22 kcal/mol with Phe443 of MHC-II, compared to -6.03 kcal/mol and -5.619 kcal/mol for cyclic peptides 0 and 5, respectively. Despite promising in vitro results, cyclic peptide 12 failed to inhibit tumor growth in vivo, underscoring the importance of dual immunotherapies targeting several immune checkpoints to achieve anti-tumor efficacy.

2024-07-01·CURRENT TREATMENT OPTIONS IN ONCOLOGY

Neoadjuvant Immunotherapy in Non-melanoma Skin Cancers of the Head and Neck

Review

作者: Ezzibdeh, Rami ; Diop, Mohamed ; Divi, Vasu

OPINION STATEMENT:

Neoadjuvant immunotherapy will change the standard of care for advanced resectable cutaneous squamous cell carcinoma (cSCC) and possibly other non-melanoma skin cancers. With pathological complete response rates around 50% for cSCC in early studies, neoadjuvant therapy allows patients the possibility of significant reduction in tumor size, de-escalation of adjuvant therapy, and improved long-term outcomes. Patients must be carefully selected to ensure that there is a margin of safety with respect to resectability, such that if a tumor progresses on neoadjuvant therapy, there remains a curative surgical option that is acceptable to the patient. The optimal treatment paradigm is an area of active research, with many researchers questioning whether adjuvant therapy, or even local therapy, is necessary in patients who seem to have a complete response. The ability to predict who will respond will become even more critical to answer, as a significant number of patients do not want to risk their disease progressing, especially in cosmetically sensitive areas of the head and neck. Recent studies in melanoma show promise for improved response rates using combination therapies, and these strategies may apply to cSCC as well. The use of LAG-3 inhibitors or mRNA vaccine technology may further improve the utility of neoadjuvant strategies.

项与 LAG-3 checkpoint inhibitor(argenx SE) 相关的新闻（医药）

2024-12-05

·drugs

Black Patients Have Similar Immune Checkpoint Inhibitor Effectiveness, Lower Toxicity

THURSDAY, Dec. 5, 2024 -- Black patients have similar immune checkpoint inhibitor (ICI) effectiveness and lower toxicities compared with White patients, according to a study published online Nov. 14 in The Lancet Oncology . Sean Miller, M.D., from the Veterans Affairs Ann Arbor Healthcare System in Michigan, and colleagues conducted a retrospective cohort study to characterize the effectiveness and safety of ICIs in Black patients. All patients in the U.S. Veterans Health Administration system Corporate Data Warehouse who self-identified as non-Hispanic Black or African American or non-Hispanic White and received PD-1, PD-L1, CTLA-4, or LAG-3 inhibitors between Jan. 1, 2010, and Dec. 31, 2023, were included. Data were included for 26,398 patients: 18.7 percent Black and 81.3 percent White. The researchers found that Black patients had longer time to treatment discontinuation compared with White patients (two-year unadjusted rates, 10.7 versus 8.6 percent; adjusted hazard ratio, 0.91); similar time to next treatment (23.5 versus 25.6 percent for White patients); and slightly improved overall survival (36.5 versus 36.5 percent for Black versus White patients; hazard ratio, 0.95). Black patients had a reduced risk for all-grade immune-related adverse events compared with White patients; immune-related adverse events requiring treatment with systemic steroids; and immune-related adverse events resulting in permanent ICI discontinuation (adjusted hazard ratios, 0.75, 0.61, and 0.58, respectively). "To our knowledge, this study is the largest analysis of ICI efficacy and safety in Black patients to date, a population severely under-represented in ICI clinical trials, and raises crucial questions regarding the reasons for lower observed immune-related adverse events than in White patients," the authors write.

免疫疗法临床结果

2023-06-21

·GlobeNewswire-Health Care

argenx Announces U.S. Food and Drug Administration Approval of VYVGART Hytrulo (efgartigimod alfa and hyaluronidase-qvfc) Injection for Subcutaneous Use in Generalized Myasthenia Gravis

VYVGART® Hytrulo is first FDA-approved subcutaneous (SC) injectable for generalized myasthenia gravis (gMG) With this approval, argenx broadens innovative gMG product offering and demonstrates continued commitment to providing more choice and flexibility for patients Efficacy of VYVGART Hytrulo was established by demonstrating a comparable pharmacodynamic (PD) effect to VYVGART® in Phase 3 ADAPT-SC bridging study Management to host conference call tomorrow at 2:30pm CET (8:30 am ET) argenx SE (Euronext & Nasdaq: ARGX), a global immunology company committed to improving the lives of people suffering from severe autoimmune diseases, today announced that the U.S. Food and Drug Administration (FDA) approved VYVGART® Hytrulo (efgartigimod alfa and hyaluronidase-qvfc). VYVGART Hytrulo is an injection for subcutaneous (SC) use for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody positive. These patients represent approximately 85% of the total gMG population. VYVGART Hytrulo is a subcutaneous product combination of efgartigimod alfa, a human IgG1 antibody fragment marketed for intravenous use as VYVGART, and recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE® drug delivery technology to facilitate subcutaneous delivery of biologics. The product is to be administered subcutaneously by a healthcare professional as a single injection (1,008 mg fixed dose) over 30-90 seconds in cycles of once weekly injections for four weeks. “Today’s approval of VYVGART Hytrulo is another significant milestone on our path to redefine what well-controlled means for gMG patients. The availability of a second argenx innovation in just 18 months also underscores our longstanding commitment to the gMG community by providing more choice and flexibility in how patients receive treatment,” said Luc Truyen M.D., Ph.D., Chief Medical Officer, argenx. “With our broad gMG offering of both a first-in-class infusion and SC injection, we continue to offer an individualized treatment approach and possibility of staying symptom free, while providing patients options of how and where they want to seek treatment. We want to thank the gMG patient community and their supporters, clinical investigators, our employees and all stakeholders who have collaborated with us to advance this subcutaneous option, including our partners at Halozyme.” “The availability of another gMG treatment option from argenx, now in a subcutaneous delivery, is a meaningful advancement for the patient community. Patients now have the opportunity to receive treatment in an infusion center, at home or at a physician’s office - providing more flexibility and freedom of choice that can make daily living easier for gMG patients and their caregivers,” said Allison Foss, Executive Director of the Myasthenia Gravis Association. Phase 3 ADAPT-SC Bridging Study “The clinical trials of VYVGART continue to show significant benefit to patients with a favorable safety profile and clear improvements in gMG disease scores. Now with the approval of VYVGART Hytrulo, we have a broad gMG treatment offering with both IV and SC administration options and can select based on patient needs and preference without sacrificing clinical benefit or safety,” said James F. Howard Jr., M.D., Professor of Neurology (Neuromuscular Disease), Medicine and Allied Health, Department of Neurology, The University of North Carolina at Chapel Hill School of Medicine and Principal Investigator for the ADAPT-SC trial. This FDA approval is based on positive results from the Phase 3 ADAPT-SC study, which established the efficacy of VYVGART Hytrulo by demonstrating a reduction in anti-AChR antibody levels comparable to intravenous VYVGART in adult gMG patients. ADAPT-SC was a bridging study to the Phase 3 ADAPT study, which formed the basis for approval of intravenous VYVGART in December 2021. In the ADAPT-SC study, the primary endpoint of noninferiority was met (p VYVGART Hytrulo has a demonstrated safety profile, consistent with the ADAPT clinical trial with the exception of injection site reactions (ISRs), which were higher with VYVGART Hytrulo. It was generally well-tolerated with ISRs being the most frequent adverse events. All ISRs, which are commonly observed with biologics administered subcutaneously, were mild to moderate, and resolved over time. Access to VYVGART Hytrulo VYVGART Hytrulo is expected to be available for patients in the U.S. in July 2023. argenx is committed to supporting access for patients to its medicines and has decided to price VYVGART Hytrulo at parity to VYVGART on a net annual revenue basis. Throughout their treatment journey, patients can access VYVGART Hytrulo in the same personalized way they access VYVGART today with support from My VYVGART Path. Program resources include disease and product education, access support and benefits verification, and financial assistance programs for eligible patients. Patients and clinicians can access more information at VYVGARTHytrulo.com. Marketing authorization applications for SC efgartigimod are under review by the European Medicines Agency with a decision expected by the end of 2023, and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) with a decision expected by the first quarter of 2024. About Phase 3 ADAPT-SC Trial The Phase 3 ADAPT-SC trial was a multicenter, randomized, open-label, parallel-group study evaluating the noninferiority of the pharmacodynamic (PD) effect of VYVGART Hytrulo compared with VYVGART in adult patients with gMG. The pharmacodynamic effect was measured by percent change from baseline in autoantibody (AChR) levels at day 29. Safety, clinical efficacy, immunogenicity and pharmacokinetics (PK) were also assessed. A total of 110 adult patients with gMG in North America, Europe and Japan enrolled in the ADAPT-SC trial. Patients were randomized in a 1:1 ratio to receive VYVGART Hytrulo or VYVGART for one treatment cycle consisting of four doses at once-weekly intervals. The total study duration was approximately 12 weeks, including seven weeks of follow-up after the treatment cycle. At the completion of ADAPT-SC, patients had the opportunity to roll-over to ADAPT-SC+, an open-label extension study. About VYVGART® Hytrulo VYVGART Hytrulo is a subcutaneous combination of efgartigimod alfa, a human IgG1 antibody fragment marketed for intravenous use as VYVGART®, and recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE® drug delivery technology to facilitate subcutaneous injection delivery of biologics. In binding to the neonatal Fc receptor (FcRn), VYVGART Hytrulo results in the reduction of circulating IgG. It is the first-and-only approved FcRn blocker administered by subcutaneous injection. About Generalized Myasthenia Gravis Generalized myasthenia gravis (gMG) is a rare and chronic autoimmune disease where IgG autoantibodies disrupt communication between nerves and muscles, causing debilitating and potentially life-threatening muscle weakness. Approximately 85% of people with MG progress to gMG within 24 months, where muscles throughout the body may be affected. Patients with confirmed AChR antibodies account for approximately 85% of the total gMG population. About argenx argenx is a global immunology company committed to improving the lives of people suffering from severe autoimmune diseases. Partnering with leading academic researchers through its Immunology Innovation Program (IIP), argenx aims to translate immunology breakthroughs into a world-class portfolio of novel antibody-based medicines. argenx developed and is commercializing the first-and-only approved neonatal Fc receptor (FcRn) blocker in the U.S., Japan, Israel, the EU and the UK. The Company is evaluating efgartigimod in multiple serious autoimmune diseases and advancing several earlier stage experimental medicines within its therapeutic franchises. For more information, visit www.argenx.com and follow us on LinkedIn, Twitter, and Instagram. The content above comes from the network. if any infringement, please contact us to modify.