Cutting-Edge: Preclinical and Clinical Development of Opdualag: Comparison
View Latest Version
Please note this is a comparison between Version 4 by Beatrix Zheng and Version 3 by Beatrix Zheng.

Immune checkpoint inhibitors (ICIs) have revolutionized medical practice in oncology since the FDA approval of the first ICI 11 years ago. In light of this, Lymphocyte-Activation Gene 3 (LAG-3) is one of the most important next-generation immune checkpoint molecules, playing a similar role as Programmed cell Death protein 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4). 19 LAG-3 targeting molecules are being evaluated at 108 clinical trials which are demonstrating positive results, including promising bispecific molecules targeting LAG-3 simultaneously with other ICIs. Recently, a new dual anti-PD-1 (Nivolumab) and anti-LAG-3 (Relatimab) treatment developed by Bristol Myers Squibb (Opdualag), was approved by the Food and Drug Administration (FDA) as the first LAG-3 blocking antibody combination for unresectable or metastatic melanoma. This novel immunotherapy combination more than doubled median progression-free survival (PFS) when compared to nivolumab monotherapy (10.1 months versus 4.6 months).

  • opdualag
  • relatimab
  • BMS-986016
  • nivolumab
  • LAG-3
  • PD-1

1. LAG-3 Molecular Function

The LAG-3 molecule has recently emerged as a promising cancer immunotherapy target and a highly important next-generation immune checkpoint molecule [1][2][3]. Closely related to CD4, and adjacent to its locus, it presents a similar genetic organization [4]. LAG-3 was first described as an immune inhibitory receptor in activated T cells. It plays a similar role than its immune-checkpoint counterparts PD-1 and CTLA-4 [5][6]. LAG-3 exerts an inhibitory function over multiple biological functions, such as T cell activation, immune function, proliferation, cytokine secretion, effector functions and T cell homeostasis [5][6][7][8][9]. For example, LAG-3 regulates the size of the expanding T cell population following antigen activation in vivo [8]. In broad terms, LAG-3 down-modulates TCR:CD3 intracellular signal transduction cascades and calcium fluxes within the immunological synapse, terminating cytokine and T cell responses to the TCR:CD3 activation, while favouring CD4 and CD8 T cell exhaustion [8][10][11][12][13][14][15].
LAG-3 is expressed by many T cell subsets, including: CD4 T helper cells, cytotoxic CD8 T cells, activated T cells, NK T cells, effector CD4 T cells, regulatory T cells, CD8 tumor-infiltrating lymphocytes and tumor-infiltrating antigen-specific CD8 T cells [4][16][17][18][19][20][21][22][23][24][25][26][27]. However, LAG-3 expression is not limited to T cells, having been described in B cells, natural regulatory plasma cells or B cells, plasmacytoid dendritic cells (DCs) and in neurons among others [15][27][28][29][30][31].
Initially, its high-affinity binding with the class II Major Histocompatibility Complex (MHC-II) was considered to mediate its inhibitory functions. MHC-II was thought to be its canonical ligand. MHC-II binds to LAG-3 with higher affinity than CD4, thus inhibiting CD4 T cell activation by competition with its binding to CD4 [5][6][32][33][34][35][36]. However, while it is undeniable that LAG-3:MHC-II interaction plays a critical role, LAG-3 binding to other ligands contributes to its inhibitory activities. The next functional ligands to be described were galectin-3 (Gal-3), critical to inhibit T cell activation and CD8 cytotoxic T cell functions [37][38][39][40], the liver-secreted protein fibrinogen-like protein 1 (FGL1), critical for tumor immune evasion mechanisms in response to anti-PD-1/anti-PD-L1 treatments [9][37][41][42][43], and the DC-specific Intercellular adhesion molecule-3-grabbing non-integrin family member (LSECtin) in melanoma cells, inhibiting cyclin-dependent kinases [44].

2. LAG-3 Clinical Research

LAG-3 is generally considered an aggressive progression marker in several haematological and solid malignancies, driving T cell exhaustion and pro-apoptosis, and associated with poor prognosis and decreased survival. Its expression is also considered an intrinsic resistance mechanism to anti-PD-1/anti-PD-L1 therapies through its synergic co-expression with PD-1 [12][22][45][46][47][48][49][50][51][52]. For example, non-small cell lung cancer (NSCLC) patients who did not respond to anti-PD-L1/PD-1 monotherapies had highly dysfunctional T cells that strongly co-expressed PD-1 and LAG-3 after TCR stimulation [22]. ICB therapies, especially anti-PD-1/anti-PD-L1 treatments, have revolutionized cancer treatment in recent years. However, not all patients respond to treatment due to intrinsic or extrinsic resistance mechanisms [1]. LAG-3 over-expression confers resistance to PD-1 blockade. Indeed, PD-1/LAG-3 co-blockade is demonstrating encouraging results and strong capacities both in preclinical and clinical research [2]. In this context, LAG-3-targeted therapies have emerged as a cancer immunotherapy alone and in combination with anti-PD-1 treatments. A new generation of novel bispecific molecules is being evaluated with encouraging results in preclinical and clinical studies.
108 interventional clinical trials are evaluating 19 different LAG-3 targeting molecules in 39 phase I trials, 2 phase I/II trials, 40 phase II trials, 3 phase II/III trials and 3 phase III trials. These molecules can be divided into anti-LAG-3 monoclonal antibodies (178 trials, 10 molecules), bispecific molecules (14 trials, 7 molecules), LAG-3 fusion proteins (15 trials, 2 molecules) and CAR-T cells (1 trial, 1 molecule). In total, more than 28,000 adult patients are being enrolled with the exception of the NCT03470922 phase II/III trial, which is enrolling patients of 12 years old patients and older. A total of 23 trials are active but not recruiting, 16 are completed, 8 not yet recruiting, 49 recruiting, 9 terminated and 2 withdrawn. Only 13 have available results. According to allocation, 50 trials are randomized, 39 non-randomized, and 19 N/A. On the intervention model, 68 trials follow a parallel assignment, 1 a crossover assignment, 25 a single group assignment and 13 a sequential assignment. Most of them follow an open label masking, while three of them a single (participant), four a double (participant and investigator), two a triple (participant, care provider and investigator) and four a quadruple (participant, care provider, investigator and outcomes assessor) (Figure 1 and Figure 2). Treated neoplasias include most hematological and solid cancers, but also psoriasis, ulcerative colitis and influenza.
/media/item_content/202208/62f308eb5ef8ccells-11-02351-g001.png
Figure 1. LAG-3-targeted therapy clinical landscape allocation, intervention models and masking of LAG-3 targeted molecules including LAG-3 fusion proteins, bispecific molecules and monoclonal antibodies (https://clinicaltrials.gov/, accessed on 29 June 2022). Percentages are indicated within the graphs.
/media/item_content/202208/62f309272f567cells-11-02351-g002.png
Figure 2. LAG-3-targeted therapy clinical landscape of phases for anti-LAG-3 monoclonal antibodies, bispecific molecules and fusion proteins clinically developed (https://clinicaltrials.gov/, accessed on 29 June 2022).
Interestingly, LAG-3 expression is associated with increased pathology and impaired immune responses in multiples diseases such as Parkinson’s Disease [29][30], cardiovascular diseases (increased coronary heart disease and increased myocardial infarction) [53][54], HDL Hypercholesterolemia [55][56], Inflammatory Bowel Disease [57][58], Multiple Sclerosis [59], Diabetes Mellitus [60][61] and infection (Salmonella [31], Plasmodium parasites (P. yoelii 17XL, P yoelii 17XNL, P. chabaudi, P. vinckei, and P. berghei) [62], Mycobacterium tuberculosis [63], human immunodeficiency virus (HIV) [64], non-pathogenic simian immunodeficiency virus (SIV) [65], hepatitis B virus (HBV) [66], human papillomavirus (HPV) [67], hepatitis C virus (HCV) [67], lymphocytic choriomeningitis viral (LCMV), herpes simplex virus 1 (HSV-1) and other chronic viral infections [15][68][69][70][71][72]. Thus, LAG-3 targeted strategies currently under clinical development for cancer will also be relevant as immunotherapies for the treatment of non-neoplastic diseases [73][74][75][76][77].

2.1. Anti-LAG-3 Monoclonal Antibodies

78 clinical trials are evaluating 10 different anti-LAG-3 monoclonal antibodies: BMS-986016 or relatlimab (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), HLX26 (Fosun Pharma), IBI110 (Innovent Biologics), INCAGN02385 (Incyte), LAG525 or IMP701 (Novartis), MK-4830 or favezelimab (Merck), REGN3767 or fianlimab (Regeneron Pharmaceuticals and Sanofi), Sym022 (Symphogen), TSR-033 (Tesaro). Of these, 21 are phase I, 19 phase I/II, 24 phase II, 1 phase II/III and 3 phase III. 7 phase I and II trials are only evaluating the anti-LAG-3 treatment alone (NCT05078593, NCT03489369, NCT03965533, NCT02195349, NCT05039658, NCT03538028, NCT03893565), 10 phase I, I/II and III trials are evaluating the anti-LAG-3 treatment alone and in combination with other ICIs (NCT02658981, NCT03250832, NCT03005782, NCT02966548, NCT02720068, NCT04150965, NCT01968109, NCT02061761, NCT02460224, NCT03743766) and the rest are evaluating anti-LAG-3 treatments in combination with other treatments, mainly with additional ICIs such as anti-PD-1. Most of them are fully humanized IgG4 blocking antibodies.
  • BMS-986016 or relatlimab, developed by Bristol-Myers Squibb in 47 clinical trials, was the first anti-LAG-3 monoclonal antibody to be clinically developed and the first one to receive the FDA approval for its clinical use. It has 4 subunits, with 16 disulfide links and 2 N-glycosylation sites, with an average molecular weight of 145.3 kDa [78]. Phase I (7 trials), I/II (12 trials), II (26 trials), II/III (1 trial) and III (1 trial) preliminary results showed good tolerability, efficacy, toxicity and antitumour profiles alone or in combination with anti-PD-1/PD-L1 blockade immunotherapies, as a good alternative to overcome immunotherapy resistance [79][80][81]. For example, it restores T cell mediated responses and TNF-a, IFN-y and IL-2 cytokine release [82]. The phase III clinical trial that led to the LAG-3/PD-1 combination approval for melanoma treatment is further discussed in the next section.
  • GSK2831781, derived from IMP731 Immunetep’s antibody, developed in monotherapy by GlaxoSmithKline in 3 clinical trials (2 phase I and 1 phase II) for psoriasis and ulcerative colitis. The ulcerative colitis phase II trial was terminated after an interim analysis [83], but phase I results show good tolerability, safety and inflammation regulation profiles [84].
  • HLX26, developed by Fosun Pharma in 2 phase I clinical trials (NCT05078593 and NCT05400265), where its safety, tolerability, pharmacokinetic characteristics and preliminary efficacy are being evaluated alone and in combination with anti-PD-1 treatments in patients with solid tumors or lymphoma.
  • IBI110, developed by Innovent Biologics in a phase I clinical trial alone and in combination with anti-PD-1 in patients with relapsed or refractory diffuse large B cell lymphoma (r/r DLBCL) (NCT05039658).
  • INCAGN02385, is being developed by Incyte in 4 clinical trials (1 phase I, 1 phase I/II and 2 phase II) alone (NCT03538028) or in combination (NCT04370704, NCT05287113, NCT04586244) with anti-PD-1 and anti-TIM-3 immune checkpoint therapies. Preliminary data shows good tolerability profiles [85].
  • LAG525 or IMP701 developed by Novartis in 5 clinical trials (1 phase I, 1 phase I/II and 3 phase II), alone or in combination with anti-PD-1 blockers. The structure of this antibody consists of 4 subunits, 16 disulfide bridges and 2 N-glycosylation sites, with an estimated molecular weight of 147 kDa [86]. Preliminary data demonstrate promising pharmacokinetics, antitumour activity and safety alone and in combination [87][88][89].
  • MK-4830 or favezelimab, developed by Merck in 8 clinical trials (1 phase I, 5 phase I/II, 1 phase II and 1 phase III), alone or in combination with anti-PD-1, oxaliplatin, Leucovorin (Calcium Folinate), Fluorouracil [5-FU] and lenvatinib, showing manageable safety and tolerability alone and in combination. In fact, anti-LAG-3/anti-PD-1 combination showed a 6.3% objective response rate, better than the monotherapy treatment, with similar treatment-related adverse effects [90][91]. The structure of this antibody consists of 4 subunits, 16 disulfide bridges and 2 glycosylation sites, with an estimated molecular weight of 146 kDa [92].
  • REGN3767 or fianlimab, developed by Regeneron Pharmaceuticals and Sanofi in 3 clinical trials (1 phase I, 1 phase II and 1 phase III), promotes T cell activation and T cell mediated cytotoxicity with good pharmacokinetics and toxicology profiles in vitro and in vivo [93]. The structure of the antibody is composed of 4 subunits, 16 sulfide bridges and 2 N-glycosilation sites [94]. Early efficacy and antitumor activity were also suggested in the preliminary clinical trials results. Its combination with cemiplimab also showed a good safety profile [95][96][97]. The combination with anti-PD-1, and cemiplimab is being evaluated in phase I (NCT03005782), II (NCT01042379) and III (NCT05352672) trials while it is being studied alone in the NCT03005782 phase I trial. Interestingly, anti-LAG-3 PET tracers (89Zr-DFO-REGN3767) are being clinically developed to establish the tracer biodistribution and dosimetry, monitoring the response to REGN3767 treatment (NCT05346276, NCT04706715, NCT04566978). However, these clinical trials are not being considered in this research as LAG-3 targeting clinical trials, because their main purpose is establishing PET scanning as a diagnostic method.
  • Sym022, developed by Symphogen in 3 phase I clinical trials, is being evaluated for dose-escalation and dose-expansion alone (NCT03489369) or in combination (NCT03311412, NCT04641871) with anti-PD-1 and anti-TIM-3 immunotherapies. The treatment combination showed synergic antitumor activity in preclinical models [98][99].
  • TSR-033, is being developed by Tesaro in 2 phase I clinical trials, alone and in combination with anti-PD-1 and anti-TIM-3 treatments (NCT03250832, NCT02817633). The combination with PD-1 blockers increases CD4 T cell activation and IL-2 production and cell proliferation [100]. Phase I preliminary data indicates good safety and tolerability.

2.2. Anti-LAG-3 Bispecific Antibodies

  • ABL501 is being developed by ABL Bio in a phase I trial for the treatment of any progressive, locally advanced (unresectable) or metastatic solid tumor (NCT05101109). This bispecific antibody blocks PD-L1 and LAG-3 as a single agent. Dose-escalation analysis is being conducted. The dosing interval to be used in the dose-expansion part will be re-evaluated based on the emerging safety and pharmacokinetics data from the dose-escalation part of the research. It promotes enhanced human T cell activation in vitro and potentiates antitumor responses of T cells through DC activation [101][102].
  • IBI323, a LAG-3/PD-L1 bispecific antibody, is being developed by Innovent Biologics in a phase I clinical trial alone and in combination with chemotherapy in patients with advanced malignancies. The purpose of this resesarch is to evaluate IBI323 safety, tolerability and efficacy. It enhances tumor-specific immunity in vitro [103].
  • MGD013 or Tebotelimab, a LAG-3/PD-1 bispecific DART® antibody, is being developed by MacroGenetics in 7 clinical trials (3 phase I, 1 phase I/II, 1 phase II and 2 phase II/III) in patients with unresectable or metastatic neoplasms (NCT03219268), patients with advanced or metastatic solid tumors who failed prior treatment (NCT04178460), melanoma (NCT04653038), liver cancer (NCT04212221), Head and Neck Cancer (NCT04634825, NCT04082364) and HER2+ Gastric/GEJ Cancer (NCT04082364), to evaluate its safety and efficacy, alone or in combination with margetuximab (anti-HER2), niraparib (a selective PARP1/2 inhibitor), Brivanib Alaninate (Multitargeted tyrosine kinase inhibitor) and enoblituzumab (Anti-B7-H3 antibody). Preliminary results showed good tolerability, safety and antitumour activity profiles [104].
  • RO7247669, a LAG-3/PD-1 bispecific antibody, is being developed by Hoffmann-La Roche in 1 phase I and 1 phase II clinical trials in patients with advanced and/or metastatic solid tumors (NCT04140500) and advanced or metastatic squamous cell carcinoma of the oesophagus (NCT04785820), alone or in combination with a PD-1/TIM-3 bispecific antibody or an anti-PD-1 single agent.
  • XmAb®22841 or pavunalimab, a LAG-3/CTLA-4 bispecific antibody, is being developed by Xencor in a phase I clinical trial (NCT03849469), alone and in combination with anti-PD-1 as a single agent in selected advanced solid tumors. It enhances antitumor activity, T cell activation, cytokine secretion and cell proliferation [105].
  • EMB-02, a LAG-3/PD-1 bispecific antibody, is being developed as a single treatment agent by EpimAb Biotherapeutics in a phase I/II clinical trial (NCT04618393) in advanced solid tumors. Dose escalation followed by cohort expansion will be performed. In vivo preclinical data showed antitumor activity in anti-PD-1 resistant models.
  • FS118, a LAG-3/PD-L1 bispecific antibody, is being developed as a single agent treatment by F-star Therapeutics in a phase I/II clinical trial (NCT03440437) in patients with advanced malignancies, to determine dosing and toxicity. It enhanced T cell activation and antitumor activity in vitro and in vivo [105][106][107]. Preliminary clinical trial data showed good pharmacodynamics and tolerability profiles. [108][109].
  • CB213 Humabody®, a PD-1xLAG-3 antagonist developed by Crescendo Biologics Ltd., have recently entered a partnership with Cancer Research UK for its clinical development into a future phase I clinical trial ([110]). This bispecific molecule binds and blocks with high affinity PD1 and LAG-3 on PD-1+LAG-3+ T cells, induces ex vivo T cell proliferation of dysfunctional T cells from NSCLC patients, with superior activity than anti-PD-1 alone and suppress tumor growth in vivo [111].

2.3. LAG-3 Fusion Proteins

Two different LAG-3 fusion proteins are being developed in several phase I (9), I/II (2), and II (4) trials: IMP321 or Eftilagimod Alpha or Efti (Immutep) and EOC202 (Taizhou EOC Pharma). EOC202 is a recombinant human LAG-3 fusion protein injection combined with albumin-bound paclitaxel for the treatment of patients with HR+, HER2- advanced breast cancer with progression after endocrine therapy (NCT05322720). On the other hand, IMP321 is the only soluble recombinant form of LAG-3 that is being clinically developed. In fact, IMP321 was the first LAG-3 targeted molecule to be studied in the clinic in 2006.
  • IMP321, Eftilagimod Alpha or Efti, a LAG-3 soluble fusion protein, is being developed by Immutep in 14 clinical trials (9 phase I, 2 phase I/II and 3 phase II) for the treatment of advanced solid tumors, hepatitis B and flu. IMP321 is being developed as an adjuvant and immune modulator for cancer and vaccines against infectious diseases, as well as an anticancer treatment agent. It is being tested alone and in combination with chemotherapy (gemcitabine), anti-PD-L1, anti-PD-1, paclitaxel, hepatitis B antigen (without alum), a reference flu antigen, Melan-A VLP vaccine and melanoma tumor-specific peptides. Data shows that IMP321 enhances T cell activation and proliferation, humoral, effector and adaptive immunity, cytokine release, immunogenicity and antitumor activity, with good tolerability, efficacy and safety profiles [112][113][114][115][116][117][118][119][120].
  • EOC202, a recombinant human LAG-3 fusion protein, is being developed by Taizhou EOC Pharma in a phase II clinical trial (NCT05322720) in HR+, HER2- advanced breast cancer with progression after endocrine therapy to evaluate the PFS for EOC202 combined with albumin-bound paclitaxel versus albumin-bound paclitaxel alone.

2.4. Anti-LAG-3 CAR-T Cells

One phase I/II clinical trial (NCT05410717) is evaluating Claudin6 targeting CAR-NK cells for Stage IV Ovarian Cancer, refractory testis cancer and recurrent endometrial cancer. To enhance the killing capability, some CAR-NK cells in this trial are genetically engineered to express and secret IL7/CCL19 and/or SCFVs against PD1/CTLA4/Lag3. The one study arm evaluates engineering Claudin6 targeting CAR combined with/or without IL7/CCL19 and/or scfv against PD1/CTLA4/Lag3 secreting vector into NK cells, which are isolated from patients with advanced ovarian cancer or other cancers with expression of Claudin6, and then transfusing them back the patients.

3. Opdualag and Its Pathway towards the Clinic

On 18 March2022, the FDA approved Opdualag as a first line treatment for unresectable or metastatic melanoma at a fixed dose combination. This approval signified a major historical achievement for Bristol-Myers Squibb, and a remarkable milestone for the landscape of cancer treatments. This therapeutic strategy established for the first time a next-generation LAG-3 blocker for clinical use. Opdualag consists of a pre-mixed combination of two IgG4 kappa monoclonal antibodies, nivolumab 480 mg (anti-PD-1,146 kDa) and relatlimab (BMS-98621) 160 mg (anti-LAG-3, 148 kDa) both expressed in Chinese Hamster Ovary (CHO) cell lines. This combination is prepared and provided to the patient through intravenous (IV) infusions every 4 weeks until disease progression or unacceptable toxicity occurs [121]. Its list price is $13,694.27, and it is indicated for adults and paediatric patients over the age of 12 with unresectable or metastatic melanoma that has spread or cannot be removed by surgery.
Nivolumab (opdivo) is an anti-PD-1 monoclonal antibody from Bristol-Myers Squibb clinically developed in more than 35,000 patients including Phase 3, for the treatment of a variety of tumor types. Currently approved in more than 65 countries (including the United States, the European Union, Japan and China) Opdivo was the first anti-PD-1 immune checkpoint blocker to be approved for clinical use in July 2014. Later in 2015, the combination of nivolumab with ipilimumab (Yerboy), a CTLA-4 blocking monoclonal antibody, was approved for metastatic melanoma, demonstrating to be safe and effective. In addition, preclinical and clinical studies showed that nivolumab and relatlimab combination reactivated T and NK cell-mediated responses, enhanced T cell activation and cytokine production, restoring the effector functions of exhausted T cells [82].
The FDA Oncology Center of Excellent conducted a Project Orbis review on the novel drug in collaboration with the Australian Therapeutic Goods Administration (TGA), and Switzerland’s Swissmedic to provide a review of the oncology drugs framework among international partners. This was carried out using the Real-Time Oncology Review (RTOR) pilot program to streamline data submission prior to the clinical application filing and the Assessment Aid (an applicant voluntary submission). The application by Bristol-Myers Squibb (sponsor, study director, and responsible party of the trial) was then granted priority review, fast track, and orphan drug designation [122].
Opdualag was clinically evaluated in RELATIVITY-047 (NCT03470922), an interventional multi-institutional (127 locations all over the glove), randomized (1:1), parallel assignment interventionist, quadruple-blinded (participant, care provider, investigator, outcomes assessor) phase II/III trial that enrolled 714 patients (>12 years of age). The actual research start date was 11 April 2018, the primary completion date was 25 January 2021 and the estimated research completion date is 30 November 2023. The purpose of this research is to determine whether relatlimab in combination with nivolumab is more effective than nivolumab as a monotherapy in treating unresectable melanoma or metastatic melanoma.
Inclusion criteria were histologically confirmed Stage III (unresectable) or Stage IV melanoma per the AJCC staging system, not having had prior systemic anticancer therapy for these cancers, and that tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. The two sexes were eligible for the research. Participants must have a documented BRAF status prior to randomization. Exclusion criteria were that participants must not have active brain metastases or leptomeningeal metastases, uveal melanoma, nor active, known, or suspected autoimmune disease. Healthy volunteers were not accepted. No lifestyle restrictions were required during treatment.
The primary outcome in the trial was PFS determined by Blinded Independent Central Review (BICR) using RECIST v1.1 from randomization to date of first documented tumor progression or death (up to approximately 33 months). The secondary outcome were Overall Survival (OS) and Overall Response Rate (ORR), from randomization to the date of death (up to approximately 3 years). Other outcome measures were the number of participants experiencing adverse events (AEs), serious adverse events (SAEs), AEs leading to discontinuation, laboratory abnormalities in specific liver and thyroid tests from first dose to 30 days after last dose of the research (up to approximately 33 months), as well as the number deaths from first dose up to approximately 33 months.

References

  1. De Erauso, L.C.; Zuazo, M.; Arasanz, H.; Bocanegra, A.; Hernandez, C.; Fernandez, G.; Garcia-Granda, M.J.; Blanco, E.; Vera, R.; Kochan, G.; et al. Resistance to PD-L1/PD-1 Blockade Immunotherapy. A Tumor-Intrinsic or Tumor-Extrinsic Phenomenon? Front. Pharmacol. 2020, 11, 441.
  2. Chocarro, L.; Blanco, E.; Arasanz, H.; Fernández-Rubio, L.; Bocanegra, A.; Echaide, M.; Garnica, M.; Ramos, P.; Fernández-Hinojal, G.; Vera, R.; et al. Clinical landscape of LAG-3-targeted therapy. Immunol.-Oncol. Technol. 2022, 14, 100079.
  3. Chocarro, L.; Blanco, E.; Zuazo, M.; Arasanz, H.; Bocanegra, A.; Fernández-Rubio, L.; Morente, P.; Fernández-Hinojal, G.; Echaide, M.; Garnica, M.; et al. Understanding LAG-3 Signaling. Int. J. Mol. Sci. 2021, 22, 5282.
  4. Triebel, F.; Jitsukawa, S.; Baixeras, E.; Roman-Roman, S.; Genevee, C.; Viegas-Pequignot, E.; Hercend, T. LAG-3, a novel lymphocyte activation gene closely related to CD4. J. Exp. Med. 1990, 171, 1393–1405.
  5. Huard, B.; Prigent, P.; Pagès, 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, 1180–1186.
  6. Huard, 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, 3216–3221.
  7. Andrews, L.P.; Marciscano, A.E.; Drake, C.G.; Vignali, D.A.A. LAG3 (CD223) as a cancer immunotherapy target. Immunol. Rev. 2017, 276, 80–96.
  8. Workman, C.J.; Cauley, L.S.; Kim, I.-J.; Blackman, M.A.; Woodland, D.L.; Vignali, D.A.A. Lymphocyte Activation Gene-3 (CD223) Regulates the Size of the Expanding T Cell Population Following Antigen Activation In Vivo. J. Immunol. 2004, 172, 5450–5455.
  9. Workman, C.J.; Dugger, K.J.; Vignali, D.A.A. Cutting Edge: Molecular Analysis of the Negative Regulatory Function of Lymphocyte Activation Gene-3. J. Immunol. 2002, 169, 5392–5395.
  10. Williams, J.B.; Horton, B.L.; Zheng, Y.; Duan, Y.; Powell, J.D.; Gajewski, T.F. The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment. J. Exp. Med. 2017, 214, 381–400.
  11. Huang, R.-Y.; Eppolito, C.; Lele, S.; Shrikant, P.; Matsuzaki, J.; Odunsi, K. LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling and dampen antitumor immunity in a murine ovarian cancer model. Oncotarget 2015, 6, 27359–27377.
  12. Grosso, J.F.; Goldberg, M.V.; Getnet, D.; Bruno, T.C.; Yen, H.-R.; Pyle, K.J.; Hipkiss, E.; Vignali, D.A.A.; Pardoll, D.M.; Drake, C.G. Functionally Distinct LAG-3 and PD-1 Subsets on Activated and Chronically Stimulated CD8 T Cells. J. Immunol. 2009, 182, 6659–6669.
  13. Grosso, J.F.; Kelleher, C.C.; Harris, T.J.; Maris, C.H.; Hipkiss, E.L.; De Marzo, A.; Anders, R.; Netto, G.; Getnet, D.; Bruno, T.C.; et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J. Clin. Investig. 2007, 117, 3383–3392.
  14. Chihara, N.; Madi, A.; Kondo, T.; Zhang, H.; Acharya, N.; Singer, M.; Nyman, J.; Marjanovic, N.D.; Kowalczyk, M.S.; Wang, C.; et al. Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 2018, 558, 454–459.
  15. Blackburn, S.D.; Shin, H.; Haining, W.N.; Zou, T.; Workman, C.J.; Polley, A.; Betts, M.R.; Freeman, G.J.; A A Vignali, D.; Wherry, E.J. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 2008, 10, 29–37.
  16. Camisaschi, C.; Casati, C.; Rini, F.; Perego, M.; De Filippo, A.; Triebel, F.; Parmiani, G.; Belli, F.; Rivoltini, L.; Castelli, C. LAG-3 Expression Defines a Subset of CD4+CD25highFoxp3+ Regulatory T Cells That Are Expanded at Tumor Sites. J. Immunol. 2010, 184, 6545–6551.
  17. Workman, C.J.; Vignali, D.A.A. Negative Regulation of T Cell Homeostasis by Lymphocyte Activation Gene-3 (CD223). J. Immunol. 2005, 174, 688–695.
  18. White, A.M.; Wraith, D.C. Tr1-Like T Cells—An Enigmatic Regulatory T Cell Lineage. Front. Immunol. 2016, 7, 355.
  19. Huard, B.; Tournier, M.; Triebel, F. LAG-3 does not define a specific mode of natural killing in human. Immunol. Lett. 1998, 61, 109–112.
  20. Baixeras, E.; Huard, B.; Miossec, C.; Jitsukawa, S.; Martin, M.; Hercend, T.; Auffray, C.; Triebel, F.; Piatier-Tonneau, D. Characterization of the lymphocyte activation gene 3-encoded protein. A new ligand for human leukocyte antigen class II antigens. J. Exp. Med. 1992, 176, 327–337.
  21. Huang, C.-T.; Workman, C.J.; Flies, D.; Pan, X.; Marson, A.L.; Zhou, G.; Hipkiss, E.L.; Ravi, S.; Kowalski, J.; Levitsky, H.I.; et al. Role of LAG-3 in Regulatory T Cells. Immunity 2004, 21, 503–513.
  22. Zuazo, M.; Arasanz, H.; Fernández-Hinojal, G.; García-Granda, M.J.; Gato, M.; Bocanegra, A.; Martínez, M.; Hernández, B.; Teijeira, L.; Morilla, I.; et al. Functional systemic CD 4 immunity is required for clinical responses to PD -L1/PD -1 blockade therapy. EMBO Mol. Med. 2019, 11, e10293.
  23. Matsuzaki, J.; Gnjatic, S.; Mhawech-Fauceglia, P.; Beck, A.; Miller, A.; Tsuji, T.; Eppolito, C.; Qian, F.; Lele, S.; Shrikant, 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. USA 2010, 107, 7875–7880.
  24. Bruniquel, D.; Borie, N.; Hannier, S.; Triebel, F. Regulation of expression of the human lymphocyte activation gene-3 (LAG-3) molecule, a ligand for MHC class II. Immunogenetics 1998, 48, 116–124.
  25. Annunziato, F.; Manetti, R.; Cosmi, L.; Galli, G.; Heusser, C.H.; Romagnani, S.; Maggi, E. Opposite role for interleukin-4 and interferon-γ on CD30 and lymphocyte activation gene-3 (LAG-3) expression by activated naive T cells. Eur. J. Immunol. 1997, 27, 2239–2244.
  26. Annunziato, F.; Manetti, R.; Tomasévic, I.; Giudizi, M.; Biagiotti, R.; Giannò, V.; Germano, P.; Mavilia, C.; Maggi, E.; Romagnani, S. Expression and release of LAG-3-encoded protein by human CD4 + T cells are associated with IFN-γ production. FASEB J. 1996, 10, 769–776.
  27. Bae, J.; Lee, S.J.; Park, C.-G.; Lee, Y.S.; Chun, T. Trafficking of LAG-3 to the Surface on Activated T Cells via Its Cytoplasmic Domain and Protein Kinase C Signaling. J. Immunol. 2014, 193, 3101–3112.
  28. Mao, X.; Ou, M.T.; Karuppagounder, S.S.; Kam, T.-I.; Yin, X.; Xiong, Y.; Ge, P.; Umanah, G.E.; Brahmachari, S.; Shin, J.-H.; et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 2016, 353.
  29. Angelopoulou, E.; Paudel, Y.N.; Villa, C.; Shaikh, M.F.; Piperi, C. Lymphocyte-Activation Gene 3 (LAG3) Protein as a Possible Therapeutic Target for Parkinson’s Disease: Molecular Mechanisms Connecting Neuroinflammation to α-Synuclein Spreading Pathology. Biology 2020, 9, 86.
  30. Guo, W.; Zhou, M.; Qiu, J.; Lin, Y.; Chen, X.; Huang, S.; Mo, M.; Liu, H.; Peng, G.; Zhu, X.; et al. Association of LAG3 genetic variation with an increased risk of PD in Chinese female population. J. NeuroInflamm. 2019, 16, 270.
  31. Lino, A.C.; Dang, V.D.; Lampropoulou, V.; Welle, A.; Joedicke, J.; Pohar, J.; Simon, Q.; Thalmensi, J.; Baures, A.; Flühler, V.; et al. LAG-3 Inhibitory Receptor Expression Identifies Immunosuppressive Natural Regulatory Plasma Cells. Immunity 2018, 49, 120–133.e9.
  32. Kisielow, M.; Kisielow, J.; Capoferri-Sollami, G.; Karjalainen, K. Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells. Eur. J. Immunol. 2005, 35, 2081–2088.
  33. Donia, M.; Andersen, R.; Kjeldsen, J.W.; Fagone, P.; Munir, S.; Nicoletti, F.; Andersen, M.H.; Straten, P.T.; Svane, I.M. Aberrant Expression of MHC Class II in Melanoma Attracts Inflammatory Tumor-Specific CD4+ T- Cells, Which Dampen CD8+ T-cell Antitumor Reactivity. Cancer Res. 2015, 75, 3747–3759.
  34. Hemon, P.; Jean-Louis, F.; Ramgolam, K.; Brignone, C.; Viguier, M.; Bachelez, H.; Triebel, F.; Charron, D.; Aoudjit, F.; Al-Daccak, R.; et al. MHC Class II Engagement by Its Ligand LAG-3 (CD223) Contributes to Melanoma Resistance to Apoptosis. J. Immunol. 2011, 186, 5173–5183.
  35. Huard, 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, 2718–2721.
  36. Long, L.; Zhang, X.; Chen, F.; Pan, Q.; Phiphatwatchara, P.; Zeng, Y.; Chen, H. The promising immune checkpoint LAG-3: From tumor microenvironment to cancer immunotherapy. Genes Cancer 2018, 9, 176–189.
  37. Kouo, T.; Huang, L.; Pucsek, A.B.; Cao, M.; Solt, S.; Armstrong, T.; Jaffee, E. Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells. Cancer Immunol. Res. 2015, 3, 412–423.
  38. Li, M.; Feng, Y.; Fang, S. Overexpression of ezrin and galectin-3 as predictors of poor prognosis of cervical cancer. Braz. J. Med. Biol. Res. 2017, 50, e5356.
  39. Lu, W.; Wang, J.; Yang, G.; Yu, N.; Huang, Z.; Xu, H.; Li, J.; Qiu, J.; Zeng, X.; Chen, S.; et al. Posttranscriptional regulation of Galectin-3 by miR-128 contributes to colorectal cancer progression. Oncotarget 2017, 8, 15242–15251.
  40. Chung, 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 β-catenin. Oncotarget 2014, 6, 4936–4952.
  41. Ming, Q.; Celias, D.P.; Wu, C.; Cole, A.R.; Singh, S.; Mason, C.; Dong, S.; Tran, T.H.; Amarasinghe, G.K.; Ruffell, B.; et al. LAG3 ectodomain structure reveals functional interfaces for ligand and antibody recognition. Nat. Immunol. 2022, 23, 1031–1041.
  42. Huard, B.; Mastrangeli, R.; Prigent, P.; Bruniquel, D.; Donini, S.; El-Tayar, N.; Maigret, B.; Dréano, M.; Triebel, F. Characterization of the major histocompatibility complex class II binding site on LAG-3 protein. Proc. Natl. Acad. Sci. USA 1997, 94, 5744–5749.
  43. Wang, J.; Sanmamed, M.F.; Datar, I.; Su, T.T.; Ji, L.; Sun, J.; Chen, L.; Chen, Y.; Zhu, G.; Yin, W.; et al. Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3. Cell 2019, 176, 334–347.e12.
  44. Xu, F.; Liu, J.; Liu, D.; Liu, B.; Wang, M.; Hu, Z.; Du, X.; Tang, L.; He, F. LSECtin Expressed on Melanoma Cells Promotes Tumor Progression by Inhibiting Antitumor T-cell Responses. Cancer Res. 2014, 74, 3418–3428.
  45. Zuazo, M.; Arasanz, H.; Bocanegra, A.; Chocarro, L.; Vera, R.; Escors, D.; Kagamu, H.; Kochan, G. Systemic CD4 immunity: A powerful clinical biomarker for PD-L1/PD-1 immunotherapy. EMBO Mol. Med. 2020, 12, e12706.
  46. Hernandez, C.; Arasanz, H.; Chocarro, L.; Bocanegra, A.; Zuazo, M.; Fernandez-Hinojal, G.; Blanco, E.; Vera, R.; Escors, D.; Kochan, G. Systemic Blood Immune Cell Populations as Biomarkers for the Outcome of Immune Checkpoint Inhibitor Therapies. Int. J. Mol. Sci. 2020, 21, 2411.
  47. Zuazo, M.; Arasanz, H.; Bocanegra, A.; Fernandez, G.; Chocarro, L.; Vera, R.; Kochan, G.; Escors, D. Systemic CD4 Immunity as a Key Contributor to PD-L1/PD-1 Blockade Immunotherapy Efficacy. Front. Immunol. 2020, 11, 586907.
  48. Zhang, X.; Zhao, H.; Shi, X.; Jia, X.; Yang, Y. Identification and validation of an immune-related gene signature predictive of overall survival in colon cancer. Aging 2020, 12, 26095–26120.
  49. Saka, D.; Gökalp, M.; Piyade, B.; Cevik, N.C.; Arik Sever, E.; Unutmaz, D.; Ceyhan, G.O.; Demir, I.E.; Asimgil, H. Mechanisms of T-Cell Exhaustion in Pancreatic Cancer. Cancers 2020, 12, 2274.
  50. Deng, W.-W.; Mao, L.; Yu, G.-T.; Bu, L.-L.; Ma, S.-R.; Liu, B.; Gutkind, J.S.; Kulkarni, A.B.; Zhang, W.-F.; Sun, Z.-J. LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma. OncoImmunology 2016, 5, e1239005.
  51. Datar, I.; Sanmamed, M.F.; Wang, J.; Henick, B.S.; Choi, J.; Badri, T.; Dong, W.; Mani, N.; Toki, M.; Mejías, L.D.; 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, 4663–4673.
  52. Wang, 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, 124–133.
  53. Zhu, Z.; Ye, J.; Ma, Y.; Hua, P.; Huang, Y.; Fu, X.; Li, D.; Yuan, M.; Xia, Z. Function of T regulatory type 1 cells is down-regulated and is associated with the clinical presentation of coronary artery disease. Hum. Immunol. 2018, 79, 564–570.
  54. Haudebourg, T.; Dugast, A.-S.; Coulon, F.; Usal, C.; Triebel, F.; Vanhove, B. Depletion of LAG-3 Positive Cells in Cardiac Allograft Reveals Their Role in Rejection and Tolerance. Transplantation 2007, 84, 1500–1506.
  55. Rodriguez, A. High HDL-Cholesterol Paradox: SCARB1-LAG3-HDL Axis. Curr. Atheroscler. Rep. 2021, 23, 5.
  56. Golden, D.; Kolmakova, A.; Sura, S.; Vella, A.T.; Manichaikul, A.; Wang, X.-Q.; Bielinski, S.J.; Taylor, K.D.; Chen, Y.-D.I.; Rich, S.S.; et al. Lymphocyte activation gene 3 and coronary artery disease. JCI Insight 2016, 1, e88628.
  57. Slevin, S.M.; Garner, L.C.; Lahiff, C.; Tan, M.; Wang, L.M.; Ferry, H.; Greenaway, B.; Lynch, K.; Geremia, A.; Hughes, S.; et al. Lymphocyte Activation Gene (LAG)-3 Is Associated With Mucosal Inflammation and Disease Activity in Ulcerative Colitis. J. Crohn’s Colitis 2020, 14, 1446–1461.
  58. Do, J.-S.; Visperas, A.; Sanogo, Y.O.; Bechtel, J.J.; Dvorina, N.; Kim, S.; Jang, E.; Stohlman, S.A.; Shen, B.; Fairchild, R.L.; et al. An IL-27/Lag3 axis enhances Foxp3+ regulatory T cell–suppressive function and therapeutic efficacy. Mucosal Immunol. 2015, 9, 137–145.
  59. Zhang, Z.; Duvefelt, K.; Svensson, F.; Masterman, T.; Jonasdottir, G.; Salter, H.; Emahazion, T.; Hellgren, D.; Falk, G.; Olsson, T.; et al. Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis. Genes Immun. 2005, 6, 145–152.
  60. Delmastro, M.M.; Styche, A.J.; Trucco, M.M.; Workman, C.J.; Vignali, D.A.; Piganelli, J.D. Modulation of Redox Balance Leaves Murine Diabetogenic TH1 T Cells “LAG-3-ing” Behind. Diabetes 2012, 61, 1760–1768.
  61. Bettini, M.; Szymczak-Workman, A.L.; Forbes, K.; Castellaw, A.H.; Selby, M.; Pan, X.; Drake, C.G.; Korman, A.J.; Vignali, D.A.A. Cutting Edge: Accelerated Autoimmune Diabetes in the Absence of LAG-3. J. Immunol. 2011, 187, 3493–3498.
  62. Doe, H.T.; Kimura, D.; Miyakoda, M.; Kimura, K.; Akbari, M.; Yui, K. Expression of PD-1/LAG-3 and cytokine production by CD4+T cells during infection withPlasmodiumparasites. Microbiol Immunol. 2016, 60, 121–131.
  63. Phillips, B.L.; Mehra, S.; Ahsan, M.H.; Selman, M.; Khader, S.; Kaushal, D. LAG3 Expression in Active Mycobacterium tuberculosis Infections. Am. J. Pathol. 2014, 185, 820–833.
  64. Graydon, C.G.; Balasko, A.L.; Fowke, K.R. Roles, function and relevance of LAG3 in HIV infection. PLOS Pathog. 2019, 15, e1007429.
  65. Jochems, S.P.; Jacquelin, B.; Tchitchek, N.; Busato, F.; Pichon, F.; Huot, N.; Liu, Y.; Ploquin, M.J.; Roché, E.; Cheynier, R.; et al. DNA methylation changes in metabolic and immune-regulatory pathways in blood and lymph node CD4 + T cells in response to SIV infections. Clin. Epigenetics 2020, 12, 188.
  66. Wuerdemann, N.; Pütz, K.; Eckel, H.; Jain, R.; Wittekindt, C.; Huebbers, C.U.; Sharma, S.J.; Langer, C.; Gattenlöhner, S.; Büttner, R.; et al. LAG-3, TIM-3 and VISTA Expression on Tumor-Infiltrating Lymphocytes in Oropharyngeal Squamous Cell Carcinoma—Potential Biomarkers for Targeted Therapy Concepts. Int. J. Mol. Sci. 2020, 22, 379.
  67. Li, F.-J.; Zhang, Y.; Jin, G.-X.; Yao, L.; Wu, D.-Q. Expression of LAG-3 is coincident with the impaired effector function of HBV-specific CD8+ T cell in HCC patients. Immunol. Lett. 2012, 150, 116–122.
  68. Roy, S.; Coulon, P.-G.; Srivastava, R.; Vahed, H.; Kim, G.J.; Walia, S.S.; Yamada, T.; Fouladi, M.A.; Ly, V.T.; Benmohamed, L. Blockade of LAG-3 Immune Checkpoint Combined With Therapeutic Vaccination Restore the Function of Tissue-Resident Anti-viral CD8+ T Cells and Protect Against Recurrent Ocular Herpes Simplex Infection and Disease. Front. Immunol. 2018, 9, 2922.
  69. Roy, S.; Coulon, P.-G.; Prakash, S.; Srivastava, R.; Geertsema, R.; Dhanushkodi, N.; Lam, C.; Nguyen, V.; Gorospe, E.; Nguyen, A.M.; et al. Blockade of PD-1 and LAG-3 Immune Checkpoints Combined with Vaccination Restores the Function of Antiviral Tissue-Resident CD8 + T RM Cells and Reduces Ocular Herpes Simplex Infection and Disease in HLA Transgenic Rabbits. J. Virol. 2019, 93, e00827-19.
  70. Richter, K.; Agnellini, P.; Oxenius, A. On the role of the inhibitory receptor LAG-3 in acute and chronic LCMV infection. Int. Immunol. 2009, 22, 13–23.
  71. Anderson, A.C.; Joller, N.; Kuchroo, V.K. Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity 2016, 44, 989–1004.
  72. McLane, L.M.; Abdel-Hakeem, M.S.; Wherry, E.J. CD8 T Cell Exhaustion during Chronic Viral Infection and Cancer. Annu. Rev. Immunol. 2019, 37, 457–495.
  73. Chocarro, L.; Blanco, E.; Arasanz, H.; Fernandez-Rubio, L.; Echaide, M.; Garnica, M.; Ramos, P.; Piñeiro, S.; Kochan, G.; Escors, D. LAG-3 Role in Infection. In Proceedings of the 1st International Electronic Conference on Molecular Sciences: Druggable Targets of Emerging Infectious Disease, 31 August 2021; Volume 2021.
  74. Chocarro, L.; Blanco, E.; Arasanz, H.; Fernandez-Rubio, L.; Echaide, M.; Garnica, M.; Ramos, P.; Piñeiro, S.; Kochan, G.; Escors, D. LAG-3 Role in Cardiovascular Diseases. In Proceedings of the MOL2NET’22, Conference on Molecular, Biomedical & Computational Sciences and Engineering, Basel, Switzerland, 23 March 2022.
  75. Chocarro, L.; Blanco, E.; Arasanz, H.; Fernandez-Rubio, L.; Echaide, M.; Garnica, M.; Ramos, P.; Piñeiro, S.; Kochan, G.; Escors, D. LAG-3 Role in Inflammatory Diseases. In Proceedings of the MOL2NET’22, Conference on Molecular, Biomedical & Computational Sciences and Engineering, Basel, Switzerland, 23 March 2022.
  76. Chocarro, L.; Blanco, E.; Arasanz, H.; Fernandez-Rubio, L.; Echaide, M.; Garnica, M.; Ramos, P.; Piñeiro, S.; Kochan, G.; Escors, D. LAG-3 Role in Neurological Diseases. In Proceedings of the MOL2NET’22, Conference on Molecular, Biomedical & Computational Sciences and Engineering, Basel, Switzerland, 23 March 2022.
  77. Chocarro, L.; Blanco, E.; Arasanz, H.; Fernandez-Rubio, L.; Bocanegra, A.; Echaide, M.; Garnica, M.; Ramos, P.; Piñeiro, S.; Kochan, G.; et al. Role of the next-generation immune checkpoint LAG-3 in response and resistance to cancer immunotherapy. In Proceedings of the MOL2NET’22, Conference on Molecular, Biomedical & Computational Sciences and Engineering, Basel, Switzerland, 23 March 2022.
  78. RELATLIMAB. Available online: https://drugs.ncats.io/substance/AF75XOF6W3 (accessed on 1 July 2022).
  79. Ascierto, P.A.; Melero, I.; Bhatia, S.; Bono, P.; Sanborn, R.E.; Lipson, E.J.; Callahan, M.K.; Gajewski, T.; Gomez-Roca, C.A.; Hodi, F.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.
  80. Lipson, E.; Long, G.; Tawbi, H.; Schadendorf, D.; Atkinson, V.; Maurer, M.; Simonsen, K.; Harbison, C.; Hodi, F. 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–viii465.
  81. Ascierto, P.A.; Bono, P.; Bhatia, S.; Melero, I.; Nyakas, M.S.; Svane, I.-M.; Larkin, J.; Gomez-Roca, C.; Schadendorf, D.; Dummer, R.; et al. 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–v612.
  82. Sordo-Bahamonde, C.; Lorenzo-Herrero, S.; González-Rodríguez, A.P.; Payer, Á.R.; González-García, E.; López-Soto, A.; Gonzalez, S. LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia. Cancers 2021, 13, 2112.
  83. Clinical Trials Register—Search for 2018-003278-28. Available online: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-003278-28 (accessed on 1 July 2022).
  84. Ellis, J.; Marks, D.J.; Srinivasan, N.; Barrett, C.; Hopkins, T.G.; Richards, A.; Fuhr, R.; Albayaty, M.; Coenen, M.; Liefaard, L.; et al. Depletion of LAG-3 + T Cells Translated to Pharmacology and Improvement in Psoriasis Disease Activity: A Phase I Randomized Study of mAb GSK2831781. Clin. Pharmacol. Ther. 2020, 109, 1293–1303.
  85. Savitsky, D.; Ward, R.; Riordan, C.; Mundt, C.; Jennings, S.; Connolly, J.; Findeis, M.; Sanicola, M.; Underwood, D.; Nastri, H.; et al. Abstract 3819: INCAGN02385 is an antagonist antibody targeting the co-inhibitory receptor LAG-3 for the treatment of human malignancies. Cancer Res. 2018, 78, 3819.
  86. IERAMILIMAB. Available online: https://drugs.ncats.io/substance/OI8P0SFD4R (accessed on 1 July 2022).
  87. Lin, C.-C.; Garralda, E.; Schöffski, P.; Hong, D.; Siu, L.; Martin, M.; Maur, M.; Hui, R.; Soo, R.; Chiu, J.; et al. 387 A Phase II, multicenter study of the safety and efficacy of LAG525 in combination with spartalizumab in patients with advanced malignancies. J. Immunother. Cancer 2020, 8, A412.
  88. Uboha, N.V.; Milhem, M.M.; Kovacs, C.; Amin, A.; Magley, A.; Das Purkayastha, D.; Piha-Paul, S.A. Phase II study of spartalizumab (PDR001) and LAG525 in advanced solid tumors and hematologic malignancies. J. Clin. Oncol. 2019, 37, 2553.
  89. Hong, D.S.; Schoffski, P.; Calvo, A.; Sarantopoulos, J.; De Olza, M.O.; Carvajal, R.D.; Prawira, A.; Kyi, C.; Esaki, T.; Akerley, W.L.; et al. Phase I/II study of LAG525 ± spartalizumab (PDR001) in patients (pts) with advanced malignancies. J. Clin. Oncol. 2018, 36, 3012.
  90. Garralda, E.; Sukari, A.; Lakhani, N.J.; Patnaik, A.; Lou, Y.; Im, S.-A.; Golan, T.; Geva, R.; Wermke, M.; De Miguel, M.; et al. A phase 1 first-in-human study of the anti-LAG-3 antibody MK4280 (favezelimab) plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer. J. Clin. Oncol. 2021, 39, 3584.
  91. Gregory, G.P.; Zinzani, P.L.; Palcza, J.; Healy, J.A.; Orlowski, R.J.; Nahar, A.; Armand, P. Abstract CT106: Anti-LAG-3 antibody MK-4280 in combination with pembrolizumab for the treatment of hematologic malignancies: A Phase I/II study. Cancer Res. 2019, 79, CT106.
  92. FAVEZELIMAB. Available online: https://drugs.ncats.io/substance/H1396W7D1H (accessed on 1 July 2022).
  93. Burova, E.; Hermann, A.; Dai, J.; Ullman, E.; Halasz, G.; Potocky, T.; Hong, S.; Liu, M.; Allbritton, O.; Woodruff, A.; 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, 2051–2062.
  94. FIANLIMAB. Available online: https://drugs.ncats.io/substance/OX5LRQ5H6K (accessed on 1 July 2022).
  95. Hamid, O.; Wang, D.; Kim, T.M.; Kim, S.-W.; Lakhani, N.J.; Johnson, M.L.; Groisberg, R.; Papadopoulos, K.P.; Kaczmar, J.M.; Middleton, M.R.; 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, 9515.
  96. Nanda, R.; Liu, M.C.; Yau, C.; Shatsky, R.; Pusztai, L.; Wallace, A.; Chien, A.J.; Forero-Torres, A.; Ellis, E.; Han, H.; 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, 676–684.
  97. Papadopoulos, K.P.; Lakhani, N.J.; Johnson, M.L.; Park, H.; Wang, D.; Yap, T.; Dowlati, A.; Maki, R.G.; Lynce, F.; Ulahannan, S.V.; 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, 2508.
  98. Spreafico, A.; Janku, F.; Rodon, J.A.; Tolcher, A.W.; Chandana, S.R.; Oliva, M.; Musalli, S.; Knauss, L.; Kragh, L.; Alifrangis, L.; et al. A phase I study of Sym021, an anti-PD-1 antibody (Ab), alone and in combination with Sym022 (anti-LAG-3) or Sym023 (anti-TIM-3). Ann. Oncol. 2019, 30.
  99. Lakhani, N.; Spreafico, A.; Tolcher, A.; Rodon, J.; Janku, F.; Chandana, S.; Oliva, M.; Sharma, M.; Abdul-Karim, R.; Hansen, U.; et al. 1019O Phase I studies of Sym021, an anti-PD-1 antibody, alone and in combination with Sym022 (anti-LAG-3) or Sym023 (anti-TIM-3). Ann. Oncol. 2020, 31, S704.
  100. Ghosh, S.; Sharma, G.; Travers, J.; Kumar, S.; Choi, J.; Jun, H.T.; Kehry, M.; Ramaswamy, S.; Jenkins, D. TSR-033, a novel therapeutic antibody targeting LAG-3, enhances T-cell function and the activity of PD-1 blockade in vitro and in vivo. Mol. Cancer Ther. 2019, 18, 632–641.
  101. Park, E.; Kim, H.; Sung, E.; Jung, U.; Hong, Y.; Lee, H.; Ko, M.; Park, Y.; Park, C.K.; Kim, S.J.; et al. Abstract 1633: ABL501, PD-L1 x LAG-3, a bispecific antibody promotes enhanced human T cell activation through targeting simultaneously two immune checkpoint inhibitors, LAG-3 and PD-L1. Cancer Res. 2021, 81, 1633.
  102. Sung, E.; Ko, M.; Won, J.-Y.; Jo, Y.; Park, E.; Kim, H.; Choi, E.; Jung, U.-J.; Jeon, J.; Kim, Y.; et al. LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation. Mol. Ther. 2022, 30, S1525.
  103. Jiang, H.; Ni, H.; Zhang, P.; Guo, X.; Wu, M.; Shen, H.; Wang, J.; Wu, W.; Wu, Z.; Ding, J.; et al. PD-L1/LAG-3 bispecific antibody enhances tumor-specific immunity. OncoImmunology 2021, 10, 1943180.
  104. Powderly, J.D.; Hurwitz, H.; Ryan, D.P.; Laheru, D.A.; Pandya, N.B.; Lohr, J.; Moore, P.A.; Bonvini, E.; Wigginton, J.M.; Crocenzi, T.S. A phase 1, first-in-human, open label, dose escalation study of MGD007, a humanized gpA33 × CD3 DART molecule, in patients with relapsed/refractory metastatic colorectal carcinoma. J. Clin. Oncol. 2016, 34, TPS3628.
  105. Hedvat, M.; Bonzon, C.; Bernett, M.J.; Moore, G.L.; Avery, K.; Rashid, R.; Nisthal, A.; Schubert, S.; Varma, R.; Lee, S.-H.; et al. Abstract 2784: Simultaneous checkpoint-checkpoint or checkpoint-costimulatory receptor targeting with bispecific antibodies promotes enhanced human T cell activation. Cancer Res. 2018, 78, 2784.
  106. Everett, K.L.; Kraman, M.; Wollerton, F.P.; Zimarino, C.; Kmiecik, K.; Gaspar, M.; Pechouckova, S.; Allen, N.L.; Doody, J.F.; Tuna, M. Generation of Fcabs targeting human and murine LAG-3 as building blocks for novel bispecific antibody therapeutics. Methods 2018, 154, 60–69.
  107. Kraman, M.; Faroudi, M.; Allen, N.L.; Kmiecik, K.; Gliddon, D.; Seal, C.; Koers, A.; Wydro, M.M.; Batey, S.; Winnewisser, J.; et al. FS118, a Bispecific Antibody Targeting LAG-3 and PD-L1, Enhances T-Cell Activation Resulting in Potent Antitumor Activity. Clin. Cancer Res. 2020, 26, 3333–3344.
  108. Yap, T.; Wong, D.; Hu-Lieskovan, S.; Papadopoulos, K.; Morrow, M.; Grabowska, U.; Gliddon, D.; Holz, J.-B.; LoRusso, P. 395 A first-in-human study of FS118, a tetravalent bispecific antibody targeting LAG-3 and PD-L1, in patients with advanced cancer and resistance to PD-(L)1 therapy. J. ImmunoTherapy Cancer 2020, 8, A420.
  109. Yap, T.; Papadopoulos, K.P.; Lorusso, P.; Wong, D.J.; Hu-Lieskovan, S.; Holz, J.-B. A first-in-human phase I study of FS118, an anti-LAG-3/PD-L1 bispecific antibody in patients with solid tumors that have progressed on prior PD-1/PD-L1 therapy. J. Clin. Oncol. 2019, 37, TPS2652.
  110. Crescendo Biologics and Cancer Research UK Sign Clinical Development Partnership to Develop CB213, a Novel Bispecific Humabody® Therapeutic | Business Wire. Available online: https://www.businesswire.com/news/home/20200505005080/en/Crescendo-Biologics-and-Cancer-Research-UK-sign-Clinical-Development-Partnership-to-develop-CB213-a-novel-bispecific-Humabody%C2%AE-therapeutic (accessed on 1 July 2022).
  111. Edwards, C.J.; Sette, A.; Cox, C.; Di Fiore, B.; Wyre, C.; Sydoruk, D.; Yadin, D.; Hayes, P.; Stelter, S.; Bartlett, P.D.; et al. The multi-specific VH-based Humabody CB213 co-targets PD1 and LAG3 on T cells to promote anti-tumour activity. Br. J. Cancer 2021, 126, 1168–1177.
  112. Haftcheshmeh, S.M.; Zamani, P.; Mashreghi, M.; Nikpoor, A.R.; Tavakkol-Afshari, J.; Jaafari, M.R. Immunoliposomes bearing lymphocyte activation gene 3 fusion protein and P5 peptide: A novel vaccine for breast cancer. Biotechnol. Prog. 2020, 37, e3095.
  113. Cappello, P.; Triebel, F.; Iezzi, M.; Caorsi, C.; Quaglino, E.; Lollini, P.L.; Amici, A.; Di Carlo, E.; Musiani, P.; Giovarelli, M.; et al. LAG-3 Enables DNA Vaccination to Persistently Prevent Mammary Carcinogenesis in HER-2/neu Transgenic BALB/c. Cancer Res. 2003, 63, 2518–2525.
  114. Fougeray, S.; Brignone, C.; Triebel, F. A soluble LAG-3 protein as an immunopotentiator for therapeutic vaccines: Preclinical evaluation of IMP321. Vaccine 2006, 24, 5426–5433.
  115. Andreae, S.; Piras, F.; Burdin, N.; Triebel, F. Maturation and Activation of Dendritic Cells Induced by Lymphocyte Activation Gene-3 (CD223). J. Immunol. 2002, 168, 3874–3880.
  116. Brignone, C.; Grygar, C.; Marcu, M.; Schäkel, K.; Triebel, F. A soluble form of lymphocyte activation gene-3 (IMP321) induces activation of a large range of human effector cytotoxic cells. J. Immunol. 2007, 179, 4202–4211.
  117. El Mir, S.; Triebel, F. A Soluble Lymphocyte Activation Gene-3 Molecule Used as a Vaccine Adjuvant Elicits Greater Humoral and Cellular Immune Responses to Both Particulate and Soluble Antigens. J. Immunol. 2000, 164, 5583–5589.
  118. Brignone, C.; Grygar, C.; Marcu, M.; Perrin, G.; Triebel, F. IMP321 (sLAG-3), an immunopotentiator for T cell responses against a HBsAg antigen in healthy adults: A single blind randomised controlled phase I study. J. Immune Based Ther. Vaccines 2007, 5, 5.
  119. Brignone, C.; Grygar, C.; Marcu, M.; Perrin, G.; Triebel, F. IMP321 (sLAG-3) safety and T cell response potentiation using an influenza vaccine as a model antigen: A single-blind phase I study. Vaccine 2007, 25, 4641–4650.
  120. Casati, C.; Camisaschi, C.; Rini, F.; Arienti, F.; Rivoltini, L.; Triebel, F.; Parmiani, G.; Castelli, C. Soluble Human LAG-3 Molecule Amplifies the In vitro Generation of Type 1 Tumor-Specific Immunity. Cancer Res. 2006, 66, 4450–4460.
  121. Advanced Melanoma | OpdualagTM (Nivolumab and Relatlimab-Rmbw). Available online: https://www.opdualag.com/ (accessed on 1 July 2022).
  122. FDA Approves Opdualag for Unresectable or Metastatic Melanoma. Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-opdualag-unresectable-or-metastatic-melanoma (accessed on 1 July 2022).
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
ScholarVision Creations
Feedback