Clinical landscape of LAG-3-targeted therapy
2022; Elsevier BV; Volume: 14; Linguagem: Inglês
10.1016/j.iotech.2022.100079
ISSN2590-0188
AutoresLuisa Chocarro, Ester Blanco, Hugo Arasanz, Leticia Fernández, Ana Bocanegra, Miriam Echaide, Maider Garnica, Pablo Ramos, G. Fernández-Hinojal, Ruth Vera, Grazyna Kochan, David Escors,
Tópico(s)Ubiquitin and proteasome pathways
Resumo•LAG-3 is a highly important next-generation immune checkpoint molecule.•Ninety-seven clinical trials are evaluating at least 16 LAG-3-targeting molecules.•Here we identify preclinical and clinical studies conducted involving LAG-3.•Bispecific LAG-3 molecules are being developed, showing strong capacities.•LAG-3/PD-1 co-blockade is demonstrating encouraging results. Lymphocyte-activated gene 3 (LAG-3) is a cell surface inhibitory receptor and a key regulator of immune homeostasis with multiple biological activities related to T-cell functions. LAG-3 is considered a next-generation immune checkpoint of clinical importance, right next to programmed cell death protein 1 (PD-1) and cytotoxic T-cell lymphocyte antigen-4 (CTLA-4). Indeed, it is the third inhibitory receptor to be exploited in human anticancer immunotherapies. Several LAG-3-antagonistic immunotherapies are being evaluated at various stages of preclinical and clinical development. In addition, combination therapies blocking LAG-3 together with other immune checkpoints are also being evaluated at preclinical and clinical levels. Indeed, the co-blockade of LAG-3 with PD-1 is demonstrating encouraging results. A new generation of bispecific PD-1/LAG-3-blocking agents have also shown strong capacities to specifically target PD-1+ LAG-3+ highly dysfunctional T cells and enhance their proliferation and effector activities. Here we identify and classify preclinical and clinical trials conducted involving LAG-3 as a target through an extensive bibliographic research. The current understanding of LAG-3 clinical applications is summarized, and most of the publically available data up to date regarding LAG-3-targeted therapy preclinical and clinical research and development are reviewed and discussed. Lymphocyte-activated gene 3 (LAG-3) is a cell surface inhibitory receptor and a key regulator of immune homeostasis with multiple biological activities related to T-cell functions. LAG-3 is considered a next-generation immune checkpoint of clinical importance, right next to programmed cell death protein 1 (PD-1) and cytotoxic T-cell lymphocyte antigen-4 (CTLA-4). Indeed, it is the third inhibitory receptor to be exploited in human anticancer immunotherapies. Several LAG-3-antagonistic immunotherapies are being evaluated at various stages of preclinical and clinical development. In addition, combination therapies blocking LAG-3 together with other immune checkpoints are also being evaluated at preclinical and clinical levels. Indeed, the co-blockade of LAG-3 with PD-1 is demonstrating encouraging results. A new generation of bispecific PD-1/LAG-3-blocking agents have also shown strong capacities to specifically target PD-1+ LAG-3+ highly dysfunctional T cells and enhance their proliferation and effector activities. Here we identify and classify preclinical and clinical trials conducted involving LAG-3 as a target through an extensive bibliographic research. The current understanding of LAG-3 clinical applications is summarized, and most of the publically available data up to date regarding LAG-3-targeted therapy preclinical and clinical research and development are reviewed and discussed. IntroductionLymphocyte activation gene 3 (LAG-3, CD223) is a cell surface inhibitory receptor that regulates a wide range of T-cell effector functions.1Andrews L.P. Marciscano A.E. Drake C.G. Vignali D.A. LAG3 (CD223) as a cancer immunotherapy target.Immunol Rev. 2017; 276: 80-96Crossref PubMed Scopus (431) Google Scholar, 2Chocarro L. Blanco E. 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Prigent P. Pages F. Bruniquel D. Triebel F. T cell major histocompatibility complex class II molecules down-regulate CD4+ T cell clone responses following LAG-3 binding.Eur J Immunol. 1996; 26: 1180-1186Crossref PubMed Scopus (96) Google Scholar,4Huard B. Tournier M. Hercend T. Triebel F. Faure F. Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes.Eur J Immunol. 1994; 24: 3216-3221Crossref PubMed Scopus (152) Google Scholar LAG-3 binds to MHC with higher affinity than CD4, disrupting CD4–MHC-II interactions.11Huard B. Prigent P. Tournier M. Bruniquel D. Triebel F. CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins.Eur J Immunol. 1995; 25: 2718-2721Crossref PubMed Scopus (239) Google Scholar,14Long L. Zhang X. Chen F. et al.The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy.Genes Cancer. 2018; 9: 176-189Crossref PubMed Scopus (182) Google Scholar LAG-3 binding induces MHC-II signal transduction in DCs, activating phospholipase C γ2, p72syk, PI3K/AKT, p42/44 and p38 protein kinase.15Andreae S. Buisson S. Triebel F. MHC class II signal transduction in human dendritic cells induced by a natural ligand, the LAG-3 protein (CD223).Blood. 2013; 102: 2130-2137Crossref Scopus (106) Google Scholar Engagement with Gal-3 and FGL1 also exerts T-cell inhibitory functions possibly by other means. Gal-3 can be highly expressed on tumor cells and activated T cells; it is required for CD8 T-cell and plasmacytoid DC suppression.12Kouo T. Huang L. Pucsek A.B. et al.Galectin-3 shapes anti-tumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells.Cancer Immunol Res. 2015; 3: 412-423Crossref PubMed Scopus (251) Google Scholar,16Chung L.Y. Tang S.J. Wu Y.C. Sun G.H. Liu H.Y. Sun K.H. Galectin-3 augments tumor initiating property and tumorigenicity of lung cancer through interaction with beta-catenin.Oncotarget. 2015; 6: 4936-4952Crossref PubMed Scopus (44) Google Scholar, 17Li M. Feng Y.M. Fang S.Q. Overexpression of ezrin and galectin-3 as predictors of poor prognosis of cervical cancer.Braz J Med Biol Res. 2017; 50: e5356Crossref PubMed Google Scholar, 18Lu W. Wang J. Yang G. et al.Posttranscriptional regulation of Galectin-3 by miR-128 contributes to colorectal cancer progression.Oncotarget. 2017; 8: 15242-15251Crossref PubMed Scopus (30) Google Scholar LAG-3 binding to FGL1 is non-redundant to MHC-II binding, and contribute to poor responses to anti-PD-1/anti-programmed death-ligand 1 (PD-L1) immunotherapies.13Wang J. Sanmamed M.F. Datar I. et al.Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3.Cell. 2019; 176: 334-347:e312Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar In addition, the Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin family member LSECtin acts as an LAG-3 ligand in melanoma cells, inhibiting antitumor T-cell responses by reducing the expression of CDK2, CDK4 and CDK6.19Xu F. Liu J. Liu D. et al.LSECtin expressed on melanoma cells promotes tumor progression by inhibiting anti-tumor T-cell responses.Cancer Res. 2014; 74: 3418-3428Crossref PubMed Scopus (188) Google Scholar LAG-3 inhibits T-cell receptor (TCR) signal transduction by association to the TCR–CD3 complex.20Hannier S. Tournier M. Bismuth G. Triebel F. CD3/TCR complex-associated lymphocyte activation gene-3 molecules inhibit CD3/TCR signaling.J Immunol. 1998; 161: 4058-4065PubMed Google Scholar However, the exact mechanisms of intracellular negative signal transduction are still uncharacterized.5Workman C.J. Dugger K.J. Vignali D.A. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3.J Immunol. 2002; 169: 5392-5395Crossref PubMed Scopus (215) Google Scholar,21Iouzalen N. Andreae S. Hannier S. Triebel F. 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Arasanz H. et al.55P Clinical landscape of LAG-3-targeted therapy.Ann Oncol. 2021; 32: S1362Abstract Full Text Full Text PDF Google Scholar Importantly, LAG-3 and PD-1 co-expression in T cells is a biomarker of strong T-cell dysfunctionality in cancer and it is associated with resistance to anti-PD-1/anti-PD-L1 immunotherapies.24Datar I. Sanmamed M.F. Wang J. et al.Expression analysis and significance of PD-1, LAG-3, and TIM-3 in human non-small cell lung cancer using spatially resolved and multiparametric single-cell analysis.Clin Cancer Res. 2019; 25: 4663-4673Crossref PubMed Scopus (123) Google Scholar, 25Wang Y. Dong T. Xuan Q. Zhao H. Qin L. Zhang Q. Lymphocyte-activation gene-3 expression and prognostic value in neoadjuvant-treated triple-negative breast cancer.J Breast Cancer. 2018; 21: 124-133Crossref PubMed Scopus (36) Google Scholar, 26Zuazo M. Arasanz H. 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Bocanegra A. et al.Systemic CD4 immunity as a key contributor to PD-L1/PD-1 blockade immunotherapy efficacy.Front Immunol. 2020; 11: 586907Crossref PubMed Scopus (17) Google Scholar PD-1 and LAG-3 co-blockade increases many T-cell antitumor activities.26Zuazo M. Arasanz H. Fernandez-Hinojal G. et al.Functional systemic CD4 immunity is required for clinical responses to PD-L1/PD-1 blockade therapy.EMBO Mol Med. 2019; 11e10293Crossref PubMed Scopus (91) Google Scholar,28Matsuzaki J. Gnjatic S. Mhawech-Fauceglia P. et al.Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer.Proc Natl Acad Sci U S A. 2010; 107: 7875-7880Crossref PubMed Scopus (607) Google Scholar,31Jing W. Gershan J.A. Weber J. et al.Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma.J Immunother Cancer. 2015; 3: 2Crossref PubMed Scopus (84) Google Scholar, 32Lichtenegger F.S. Rothe M. Schnorfeil F.M. et al.Targeting LAG-3 and PD-1 to enhance T cell activation by antigen-presenting cells.Front Immunol. 2018; 9: 385Crossref PubMed Scopus (94) Google Scholar, 33Lino A.C. Dang V.D. Lampropoulou V. et al.LAG-3 inhibitory receptor expression identifies immunosuppressive natural regulatory plasma cells.Immunity. 2018; 49: 120-133.e129Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar Several immunotherapies targeting LAG-3 are at various stages of clinical development.6Chocarro L. Blanco E. Arasanz H. et al.55P Clinical landscape of LAG-3-targeted therapy.Ann Oncol. 2021; 32: S1362Abstract Full Text Full Text PDF Google Scholar Here, we review the publically available data on LAG-3-targeted therapy.Preclinical and clinical development of lag-3-targeted therapySixteen LAG-3-targeted therapies are tested at 97 clinical trials by Bristol-Myers Squibb (BMS-986016), Regeneron Pharmaceuticals (REGN3767 and 89Zr-DFO-REGN3767), Merck (MK-4280), Novartis (LAG525), Tesaro (GSK) (TSR-033), Symphogen (Sym022), GlaxoSmith (GSK2831781), Incyte Biosciences International Sàrl (INCAGN02385), Prima BioMed/Immutep (IMP321), MacroGenics (MGD013), F-Star (FS118), Hoffmann-La Roche (RO7247669), Shanghai EpimAb Biotherapeutics (EMB-02), Xencor (XmAb841) and Innovent Biologics (IBI323). Figure 1 summarize the publically available data (Supplementary Table 1, available at https://doi.org/10.1016/j.iotech.2022.100079). These therapies are categorized into monoclonal antibodies, soluble LAG-3–immunoglobulin (Ig) fusion proteins and anti-LAG-3 bispecific drugs (Figure 1A). With the exception of the IgG1 antibody etigilimab, most anti-LAG-3 monoclonal antibodies are fully humanized IgG4 monoclonal blocking antibodies. IMP321 is the only soluble recombinant LAG-3 clinically studied. Additionally, bispecific anti-LAG-3-targeted drugs are being studied with very promising results, especially dual PD-1/LAG-3 blockade. Preliminary evidence from clinical trials is providing encouraging results for the treatment of cancers in terms of efficacy, safety, tolerance and pharmacokinetics.Most trials are phase I (34), I/II (21) and II (35). Few of them are early phase I (2) and phase II/III (3) trials, and only two of them have reached phase III for BMS-986016 (NCT05002569) and MK-4280 drugs (NCT05064059) (Figure 1B). All of them are interventional and investigational trials, still active and recruiting, and considered as applicable clinical trials by the Food and Drug Administration Amendments Act of 2007 (Figure 1C). Most are open-label, randomized and parallel studies (Figure 1C). The treated solid tumors are varied and summarized in Supplementary Table 1. Treated hematologic malignancies include lymphoma, myeloma and leukemia among others. Interestingly, some LAG-3 inhibitors are also being tested for psoriasis (NCT02195349), ulcerative colitis (NCT03893565), hepatitis B (NCT00354861) and influenza vaccines (Phase I Study of IMP321 Given Alone; https://clinicaltrials.gov/ct2/show/NCT00354263). As LAG-3 is involved in the pathogenesis of a wide range of non-neoplastic disease, it could be a therapeutic target for the treatment of selected pathologies. Of note, a recent controversial study with therapeutic anti-LAG-3 antibodies showed that LAG-3 is not expressed in human and murine neurons and does not modulate α-synucleinopathies.34Emmenegger M. De Cecco E. Hruska-Plochan M. et al.LAG3 is not expressed in human and murine neurons and does not modulate alpha-synucleinopathies.EMBO Mol Med. 2021; 13e14745Crossref PubMed Scopus (14) Google Scholar LAG-3 expression is included in several clinical trials as a biomarker of disease status (Supplementary Table 2, available at https://doi.org/10.1016/j.iotech.2022.100079).Anti-LAG-3 monoclonal antibodiesBMS-986016, relatlimabBMS-986016 fully human monoclonal antibody is an anti-LAG-3 fully human monoclonal IgG4-κ antibody, which was the first LAG-3 blocker to be clinically developed.35Albershardt T.C. Parsons A.J. Reeves R.S. et al.Therapeutic efficacy of PD1/PDL1 blockade in B16 melanoma is greatly enhanced by immunization with dendritic cell-targeting lentiviral vector and protein vaccine.Vaccine. 2020; 38: 3369-3377Crossref PubMed Scopus (5) Google Scholar Relatlimab binds human LAG-3 with high affinity (Kd = 0.12-0.5 nM) and inhibits its binding to MHC-II (WO 2015116539 A1).36Ascierto P.A. Bono P. Melero I. et al.LBA18 – Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with nivolumab in pts with melanoma who progressed during prior anti-PD-1/PD-L1 therapy (mel prior IO) in all-comer and biomarker-enriched populations.Ann Oncol. 2017; 28: v611-v612Abstract Full Text Full Text PDF PubMed Google Scholar,37Soldevilla M.M. Hervas S. Villanueva H. et al.Identification of LAG3 high affinity aptamers by HT-SELEX and Conserved Motif Accumulation (CMA).PLoS One. 2017; 12e0185169Crossref Scopus (22) Google Scholar Relatlimab is currently being evaluated in phase I, II, II/III and III trials in solid and hematological malignancies, alone or in combination with anti-PD-1/PD-L1 drugs6Chocarro L. Blanco E. Arasanz H. et al.55P Clinical landscape of LAG-3-targeted therapy.Ann Oncol. 2021; 32: S1362Abstract Full Text Full Text PDF Google Scholar,38Puhr H.C. Ilhan-Mutlu A. New emerging targets in cancer immunotherapy: the role of LAG3.ESMO Open. 2019; 4e000482Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar (Supplementary Table 1). Preliminary data are supporting its use either alone or in combination. It is relatively well tolerated and shows clinical efficacy.14Long L. Zhang X. Chen F. et al.The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy.Genes Cancer. 2018; 9: 176-189Crossref PubMed Scopus (182) Google Scholar,39Davar D. Zarour H.M. Immunological targets for immunotherapy: inhibitory T cell receptors.Methods Mol Biol. 2020; 2055: 23-60Crossref PubMed Scopus (8) Google Scholar Genomic and immunological differences were found between responder patients and non-responders in a combo treatment with anti-PD-1.40Jackson C. Choi J. Zhang J.J. et al.Immu-18. Immunogenomic responder phenotype from a phase I trial of anti-LAG3 or anti-CD137 alone and in combination with anti-PD-1 in patients with recurrent GBM.Neuro-Oncology. 2019; 21: vi122-vi123Crossref Google Scholar The authors monitored interferon (IFN)-γ cytokine concentrations in real time in tumor tissue biopsies, while evaluating the safety of anti-LAG-3/anti-PD-1 combination.41Lynes J. Jackson S. Sanchez V. et al.Cytokine microdialysis for real-time immune monitoring in glioblastoma patients undergoing checkpoint blockade.Neurosurgery. 2019; 84: 945-953Crossref PubMed Scopus (11) Google Scholar Relatlimab and nivolumab (anti-PD-1) combination helps in overcoming treatment resistance. For instance, preliminary results (NCT01968109; NCT03470922) showed promising initial efficacy, safety profile, well tolerability and antitumor activity in patients with melanoma in patients progressing to anti-PD-1/PD-L1 monotherapy.36Ascierto P.A. Bono P. Melero I. et al.LBA18 – Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with nivolumab in pts with melanoma who progressed during prior anti-PD-1/PD-L1 therapy (mel prior IO) in all-comer and biomarker-enriched populations.Ann Oncol. 2017; 28: v611-v612Abstract Full Text Full Text PDF PubMed Google Scholar,42Ascierto P.A. Melero I. Bhatia S. et al.Initial efficacy of anti-lymphocyte activation gene-3 (anti-LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti-PD-1/PD-L1 therapy.J Clin Oncol. 2017; 35 (:9520-9520)Crossref Google Scholar,43Lipson E.J. Long G.V. Tawbi H. et al.1302TiP – CA224-047: a randomized, double-blind, phase II/III study of relatlimab (anti-LAG-3) in combination with nivolumab (anti-PD-1) versus nivolumab alone in previously untreated metastatic or unresectable melanoma.Ann Oncol. 2018; 29: viii464-viii465Abstract Full Text Full Text PDF Scopus (0) Google Scholar Relatlimab also restores anti-leukemic T- and natural killer (NK) cell-mediated responses in patients with chronic lymphocytic leukemia. Relatlimab induces leukemic cell depletion, enhances NK and antibody-dependent cytotoxicities and promotes T-cell tumor necrosis factor (TNF)-α, IFN-γ and IL-2 cytokine.44Sordo-Bahamonde C. Lorenzo-Herrero S. Gonzalez-Rodriguez A.P. et al.LAG-3 blockade with relatlimab (BMS-986016) restores anti-leukemic responses in chronic lymphocytic leukemia.Cancers. 2021; 13: 2112Crossref PubMed Scopus (23) Google ScholarRecent phase III data on relatlimab and nivolumab combo versus nivolumab in untreated advanced melanoma showed greater benefit in progression-free survival: 47.7% at 12 months [95% confidence interval (CI), 41.8% to 53.2%] with the PD-1/LAG-3 combination as compared with 36.0% (95% CI, 30.5% to 41.6%) with the anti-PD-1 monotherapy.45Lipson E.J. Tawbi H.A. Schadendorf D. et al.Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 (CA224-047).J Clin Oncol. 2021; 39 (:9503-9503)Crossref Google Scholar,46Tawbi H.A. Schadendorf D. Lipson E.J. et al.Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma.N Engl J Med. 2022; 386: 24-34Crossref PubMed Scopus (144) Google Scholar The combo showed good toxicity profiles.REGN3767, fianlimabREGN3767 is an IgG4 fully human, hinge-stabilized, high-affinity, monoclonal antibody developed by Regeneron Pharmaceuticals. It was obtained from VelocImmune mice containing human Ig gene segments.47Macdonald L.E. Karow M. Stevens S. et al.Precise and in situ genetic humanization of 6 Mb of mouse immunoglobulin genes.Proc Natl Acad Sci U S A. 2014; 111: 5147-5152Crossref PubMed Scopus (191) Google Scholar,48Murphy A.J. Macdonald L.E. Stevens S. et al.Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice.Proc Natl Acad Sci U S A. 2014; 111: 5153-5158Crossref PubMed Scopus (239) Google Scholar Fianlimab blocks LAG-3 binding to MHC class II, activating T cells and enhancing cytotoxic T-cell-mediated tumor cell lysis (https://www.cancer.gov/publications/dictionaries/cancer-drug/def/fianlimab). REGN3767/cemiplimab (anti-PD-1) combo demonstrated good antitumor activities both in vitro and in the human PD-1xLAG-3-knockin mice model.49Burova E. Hermann A. Dai J. et al.Preclinical development of the anti-LAG-3 antibody REGN3767: characterization and activity in combination with the anti-PD-1 antibody cemiplimab in human PD-1xLAG-3-knockin mice.Mol Cancer Ther. 2019; 18: 2051-2062Crossref PubMed Scopus (30) Google Scholar Increased activation of tumor-specific T cells was observed, promoting T-cell-mediated immunity. In addition, REGN3767 showed favorable pharmacokinetics and toxicology in cynomolgus monkeys.49Burova E. Hermann A. Dai J. et al.Preclinical development of the anti-LAG-3 antibody REGN3767: characterization and activity in combination with the anti-PD-1 antibody cemiplimab in human PD-1xLAG-3-knockin mice.Mol Cancer Ther. 2019; 18: 2051-2062Crossref PubMed Scopus (30) Google Scholar Two clinical trials are investigating REGN3767 alone and in combination with anti-PD-1 inhibitors (NCT03005782, NCT01042379). In a phase I, open-label, dose-escalation and cohort expansion first-in-human clinical trial, the combination showed a safety profile similar to other immune checkpoint inhibitors (ICIs) (NCT03005782). Activity and pharmacodynamics were also examined. Preliminary data suggested a dose-dependent expansion of PD-1-expressing memory T-cell subsets by REGN3767/cemiplimab combination. Early efficacy was detected, suggesting that REGN3767 exerts antitumor activity across several tumor types. Thus, a fixed dose was selected for further evaluation.50Papadopoulos K.P. Lakhani N.J. Johnson M.L. et al.First-in-human study of REGN3767 (R3767), a human LAG-3 monoclonal antibody (mAb), ± cemiplimab in patients (pts) with advanced malignancies.J Clin Oncol. 2019; 37: 2508Crossref Google Scholar Fianlimab and cemiplimab combo showed a similar safety profile to cemiplimab alone, with one exception, and a clinical activity similar to anti-PD-1/anti-CTLA-4 combination in melanoma patients but with reduced treatment-emergent adverse events (TEAEs).51Hamid O. Wang D. Kim T.M. et al.Clinical activity of fianlimab (REGN3767), a human anti-LAG-3 monoclonal antibody, combined with cemiplimab (anti-PD-1) in patients (pts) with advanced melanoma.J Clin Oncol. 2021; 39: 9515Crossref Google Scholar Objective response rate (ORR) was 63.6% (3 complete responses and 18 partial responses) for anti-PD-L1-naïve patients and 13.3% (1 complete response and 1 partial responses) for anti-PD-L1-experienced patients. The REGN3767/cemiplimab combo is being evaluated in a phase II adaptively randomized clinical trial for breast cancer52Nanda R. Liu M.C. Yau C. et al.Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial.JAMA Oncol. 2020; 6: 676-684Crossref PubMed Scopus (236) Google Scholar (NCT01042379).89Zr-DFO-REGN3767, fianlimab tracerAnti-LAG-3 antibodies are being used for positron emission tomography (PET) scanning as a diagnostic method.53Broos K. Keyaerts M. Lecocq Q. et al.Non-invasive assessment of murine PD-L1 levels in syngeneic tumor models by nuclear imaging with nanobody tracers.Oncotarget. 2017; 8: 41932-41946Crossref PubMed Scopus (75) Google Scholar 89Zr-DFO-REGN3767 is an anti-LAG-3 PET imaging tracer that integrates the anti-LAG-3 REGN3767 antibody labeled with zirconium,54Zeglis B.M. Lewis J.S. The bioconjugation and radiosynthesis of 89Zr-DFO-labeled antibodies.J Vis Exp. 2015; 96: 52521Google Scholar used for monitoring therapy response to anti-LAG-3 treatment. This trial has several aims apart from establishing safety, pharmacokinetics, dosing and timing for PET scanning as a diagnostic method. The objectives include tumor targeting, determination of 89Zr-DFO-REGN3767 biodistribution and dosimetry, optimal time for imaging and tumor uptake after drug administration, evaluation of tumor uptake of the 89Zr-DFO-REGN3767 and correlation with LAG-3 expression (NCT04566978). This study is being carried out in early phase I and phase II imaging clinical trials for solid and hematologic cancer (NCT04706715, NCT04566978).Sym022Sym022 is a recombinant, Fc-inert, fully human, monoclonal antibody developed by Symphogen that blocks LAG-3/MHC-II binding. This antibody binds with high affinity to human and cynomolgus monkey LAG-3 and increases T-cell cytokine production.55Grandal M.M. Melander M.C. Bhatia V.K. et al.Abstract 5626: Preclinical characterization of Sym022, a novel anti-LAG3 antibody.Cancer Res. 2018; 78: 5626Crossref Google Scholar Three phase I dose-escalation and dose-expansion clinical trials are testing Sym022 for cancer treatment, alone or in combination with Sym021 (anti-PD-1) and Sym023 (anti-T-cell immunoglobulin and mucin domain-3) (NCT03489369, NCT04641871, NCT03311412). Studies in preclinical models have shown that Sym021, Sym022 and Sym023 combinations provide synergistic antitumor activities.56Spreafico A. Jank
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