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The New England Journal of Medicine Jan 2022Lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1) are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1) are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, a PD-1-blocking antibody, has been shown to be safe and to have antitumor activity in patients with previously treated melanoma, but the safety and activity in patients with previously untreated melanoma need investigation.
METHODS
In this phase 2-3, global, double-blind, randomized trial, we evaluated relatlimab and nivolumab as a fixed-dose combination as compared with nivolumab alone when administered intravenously every 4 weeks to patients with previously untreated metastatic or unresectable melanoma. The primary end point was progression-free survival as assessed by blinded independent central review.
RESULTS
The median progression-free survival was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; P = 0.006 by the log-rank test). Progression-free survival at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab-nivolumab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab-nivolumab group and in 9.7% of patients in the nivolumab group.
CONCLUSIONS
The inhibition of two immune checkpoints, LAG-3 and PD-1, provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma. Relatlimab and nivolumab in combination showed no new safety signals. (Funded by Bristol Myers Squibb; RELATIVITY-047 ClinicalTrials.gov number, NCT03470922.).
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Double-Blind Method; Female; Humans; Immune Checkpoint Inhibitors; Male; Melanoma; Middle Aged; Nivolumab; Progression-Free Survival; Lymphocyte Activation Gene 3 Protein
PubMed: 34986285
DOI: 10.1056/NEJMoa2109970 -
Clinical Cancer Research : An Official... Mar 2021The recent impressive clinical responses to antibody-based immunotherapy have prompted the identification of clinically relevant tumor antigens that can serve as targets... (Review)
Review
The recent impressive clinical responses to antibody-based immunotherapy have prompted the identification of clinically relevant tumor antigens that can serve as targets in solid tumors. Among them, B7-H3, a member of the B7 ligand family, represents an attractive target for antibody-based immunotherapy, it is overexpressed on differentiated malignant cells and cancer-initiating cells, with limited heterogeneity, and high frequency (60% of 25,000 tumor samples) in many different cancer types, but has a limited expression at low level in normal tissues. In nonmalignant tissues, B7-H3 has a predominantly inhibitory role in adaptive immunity, suppressing T-cell activation and proliferation. In malignant tissues, B7-H3 inhibits tumor antigen-specific immune responses, leading to a protumorigenic effect. B7-H3 also has nonimmunologic protumorigenic functions, such as promoting migration and invasion, angiogenesis, chemoresistance, and endothelial-to-mesenchymal transition, as well as affecting tumor cell metabolism. As a result, B7-H3 expression in tumors is associated with poor prognosis. Although experimental B7-H3 silencing reduces cancer cell malignant potential, there has been limited emphasis on the development of B7-H3-blocking antibodies, most likely because the B7-H3 receptor remains unknown. Instead, many antibody-based strategies utilizing distinct effector mechanisms to target B7-H3-expressing cancer cells have been developed. These strategies have demonstrated potent antitumor activity and acceptable safety profiles in preclinical models. Ongoing clinical trials are assessing their safety and efficacy in patients. Identification of the B7-H3 receptor will improve our understanding of its role in tumor immunity, and will suggest rational strategies to develop blocking antibodies, which may enhance the therapeutic efficacy of tumor immunity.
Topics: Antibodies, Monoclonal; B7 Antigens; Humans; Immunotherapy; Molecular Targeted Therapy; Neoplasms
PubMed: 33051306
DOI: 10.1158/1078-0432.CCR-20-2584 -
Journal of the Neurological Sciences Nov 2021The neonatal Fc receptor (FcRn) is an MHC class I-like molecule that is widely distributed in mammalian organs, tissues, and cells. FcRn is critical to maintaining... (Review)
Review
The neonatal Fc receptor (FcRn) is an MHC class I-like molecule that is widely distributed in mammalian organs, tissues, and cells. FcRn is critical to maintaining immunoglobulin G (IgG) and albumin levels through rescuing these molecules from lysosomal degradation. IgG autoantibodies are associated with many autoimmune diseases, including myasthenia gravis (MG), a rare neuromuscular autoimmune disease that causes debilitating and, in its generalized form (gMG), potentially life-threatening muscle weakness. IgG autoantibodies are directly pathogenic in MG and target neuromuscular junction proteins, causing neuromuscular transmission failure. Treatment approaches that reduce autoantibody levels, such as therapeutic plasma exchange and intravenous immunoglobulin, have been shown to be effective for gMG patients but are not indicated as ongoing maintenance therapies and can be associated with burdensome side effects. Agents that block FcRn-mediated recycling of IgG represent a rational and promising approach for the treatment of gMG. Blocking FcRn allows targeted reduction of all IgG subtypes without decreasing concentrations of other Ig isotypes; therefore, FcRn blocking could be a safe and effective treatment strategy for a broad population of gMG patients. Several FcRn-blocking antibodies and one antibody Fc fragment have been developed and are currently in various stages of clinical development. This article describes the mechanism of FcRn blockade as a novel approach for IgG-mediated disease therapy and reviews promising clinical data using such FcRn blockers for the treatment of gMG.
Topics: Animals; Autoantibodies; Histocompatibility Antigens Class I; Humans; Immunoglobulin G; Immunoglobulins, Intravenous; Myasthenia Gravis
PubMed: 34563918
DOI: 10.1016/j.jns.2021.118074 -
Journal For Immunotherapy of Cancer Apr 2022Recent advances in understanding the roles of immune checkpoints in allowing tumors to circumvent the immune system have led to successful therapeutic strategies that... (Review)
Review
Recent advances in understanding the roles of immune checkpoints in allowing tumors to circumvent the immune system have led to successful therapeutic strategies that have fundamentally changed oncology practice. Thus far, immunotherapies against only two checkpoint targets have been approved, CTLA-4 and PD-L1/PD-1. Antibody blockade of these targets enhances the function of antitumor T cells at least in part by relieving inhibition of the T cell costimulatory receptor CD28. These successes have stimulated considerable interest in identifying other pathways that may bte targeted alone or together with existing immunotherapies. One such immune checkpoint axis is comprised of members of the PVR/nectin family that includes the inhibitory receptor T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory domains (TIGIT). Interestingly, TIGIT acts to regulate the activity of a second costimulatory receptor CD226 that works in parallel to CD28. There are currently over two dozen TIGIT-directed blocking antibodies in various phases of clinical development, testament to the promise of modulating this pathway to enhance antitumor immune responses. In this review, we discuss the role of TIGIT as a checkpoint inhibitor, its interplay with the activating counter-receptor CD226, and its status as the next advance in cancer immunotherapy.
Topics: Antigens, Differentiation, T-Lymphocyte; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Neoplasms; Receptors, Immunologic; Receptors, Virus; T-Lymphocytes
PubMed: 35379739
DOI: 10.1136/jitc-2022-004711 -
Nature Oct 2022Expansion and differentiation of antigen-experienced PD-1TCF-1 stem-like CD8 T cells into effector cells is critical for the success of immunotherapies based on PD-1...
Expansion and differentiation of antigen-experienced PD-1TCF-1 stem-like CD8 T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade. Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of 'better effector' CD8 T cells similar to those generated in an acute infection. IL-2 binding to the IL-2 receptor α-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor β- and γ-chain (IL-2Rβγ)-biased agonists are currently being developed. Here we show that IL-2Rβγ-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2Rβγ on the same cell recovers the ability to differentiate stem-like CD8 T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.
Topics: Antibodies, Blocking; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Infections; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Neoplasms; Programmed Cell Death 1 Receptor; Receptors, Interleukin-2
PubMed: 36171284
DOI: 10.1038/s41586-022-05192-0 -
Cancer Immunology Research Oct 2022Novel therapeutic approaches combining immune-checkpoint inhibitors are needed to improve clinical outcomes for patients with cancer. Lymphocyte-activation gene 3...
Novel therapeutic approaches combining immune-checkpoint inhibitors are needed to improve clinical outcomes for patients with cancer. Lymphocyte-activation gene 3 (LAG-3) is an immune-checkpoint molecule that inhibits T-cell activity and antitumor immune responses, acting through an independent mechanism from that of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Here, we describe the development and preclinical characterization of relatlimab, a human antibody that binds to human LAG-3 with high affinity and specificity to block the interaction of LAG-3 with the ligands MHC II and fibrinogen-like protein-1, and to reverse LAG-3-mediated inhibition of T-cell function in vitro. Consistent with previous reports, in mouse models, the combined blockade of LAG-3 and PD-1 with surrogate antibodies resulted in enhanced antitumor activity greater than the individual blockade of either receptor. In toxicity studies in cynomolgus monkeys, relatlimab was generally well tolerated when combined with nivolumab. These results are consistent with findings from the RELATIVITY-047 phase II/III trial showing that relatlimab combined with nivolumab is a well-tolerated regimen that demonstrates superior progression-free survival compared with nivolumab monotherapy in patients with unresectable or metastatic melanoma.
Topics: Animals; Antibodies, Blocking; Antibodies, Monoclonal; CTLA-4 Antigen; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Fibrinogen; Humans; Immune Checkpoint Inhibitors; Macaca fascicularis; Melanoma; Mice; Nivolumab; Programmed Cell Death 1 Receptor
PubMed: 35981087
DOI: 10.1158/2326-6066.CIR-22-0057 -
Pharmaceutical Research Jan 2022Antibody-drug conjugates (ADCs), which are monoclonal antibodies (mAbs) conjugated with highly toxic payloads, achieve high tumor killing efficacy due to the specific...
PURPOSE
Antibody-drug conjugates (ADCs), which are monoclonal antibodies (mAbs) conjugated with highly toxic payloads, achieve high tumor killing efficacy due to the specific delivery of payloads in accordance with mAbs' function. On the other hand, the conjugation of payloads often increases the hydrophobicity of mAbs, resulting in reduced stability and increased aggregation. It is considered that mAb aggregates have potential risk for activating Fcγ receptors (FcγRs) on immune cells, and are internalized into cells via FcγRs. Based on the mechanism of action of ADCs, the internalization of ADCs into target-negative cells may cause the off-target toxicity. However, the impacts of aggregation on the safety of ADCs including off-target cytotoxicity have been unclear. In this study, we investigated the cytotoxicity of ADC aggregates in target-negative cells.
METHODS
The ADC aggregates were generated by stirring stress or thermal stress. The off-target cytotoxicity of ADC aggregates was evaluated in several target-negative cell lines, and FcγR-activation properties of ADC aggregates were characterized using a reporter cell assay.
RESULTS
Aggregation of ADCs enhanced the off-target cytotoxicity in several target-negative cell lines compared with non-stressed ADCs. Notably, ADC aggregates with FcγR-activation properties showed dramatically enhanced cytotoxicity in FcγR-expressing cells. The FcγR-mediated off-target cytotoxicity of ADC aggregates was reduced by using a FcγR-blocking antibody or Fc-engineering for silencing Fc-mediated effector functions.
CONCLUSIONS
These results indicated that FcγRs play an important role for internalization of ADC aggregates into non-target cells, and the aggregation of ADCs increases the potential risk for off-target toxicity.
Topics: Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Cell Line; Cell Line, Tumor; Humans; Immunoconjugates; Receptors, IgG
PubMed: 34961908
DOI: 10.1007/s11095-021-03158-x -
ELife Mar 2022Antibodies targeting the protein that causes placental malaria can recognise multiple variants of the protein, which may help guide the development of new vaccines to...
Antibodies targeting the protein that causes placental malaria can recognise multiple variants of the protein, which may help guide the development of new vaccines to protect pregnant women from malaria.
Topics: Antibodies, Protozoan; Female; Humans; Malaria; Malaria, Falciparum; Placenta; Pregnancy; Pregnancy Complications, Parasitic
PubMed: 35344481
DOI: 10.7554/eLife.77751 -
The Journal of Experimental Medicine Mar 2021Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there...
Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.
Topics: Angiotensin-Converting Enzyme 2; Animals; Antibodies, Blocking; COVID-19; Cerebral Cortex; Disease Models, Animal; Female; Humans; Male; Mice; Middle Aged; Neurons; Organoids; SARS-CoV-2
PubMed: 33433624
DOI: 10.1084/jem.20202135 -
ELife Sep 2022Pharmacological and genetic studies over the past decade have established the follicle-stimulating hormone (FSH) as an actionable target for diseases affecting millions,...
Pharmacological and genetic studies over the past decade have established the follicle-stimulating hormone (FSH) as an actionable target for diseases affecting millions, namely osteoporosis, obesity, and Alzheimer's disease. Blocking FSH action prevents bone loss, fat gain, and neurodegeneration in mice. We recently developed a first-in-class, humanized, epitope-specific FSH-blocking antibody, MS-Hu6, with a K of 7.52 nM. Using a Good Laboratory Practice (GLP)-compliant platform, we now report the efficacy of MS-Hu6 in preventing and treating osteoporosis in mice and parameters of acute safety in monkeys. Biodistribution studies using Zr-labeled, biotinylated or unconjugated MS-Hu6 in mice and monkeys showed localization to bone and bone marrow. The MS-Hu6 displayed a β phase t of 7.5 days (180 hr) in humanized Tg32 mice. We tested 217 variations of excipients using the protein thermal shift assay to generate a final formulation that rendered MS-Hu6 stable in solution upon freeze-thaw and at different temperatures, with minimal aggregation, and without self-, cross-, or hydrophobic interactions or appreciable binding to relevant human antigens. The MS-Hu6 showed the same level of "humanness" as human IgG1 in silico and was non-immunogenic in ELISpot assays for IL-2 and IFN-γ in human peripheral blood mononuclear cell cultures. We conclude that MS-Hu6 is efficacious, durable, and manufacturable, and is therefore poised for future human testing.
Topics: Animals; Epitopes; Excipients; Follicle Stimulating Hormone; Humans; Immunoglobulin G; Interleukin-2; Leukocytes, Mononuclear; Mice; Osteoporosis; Tissue Distribution
PubMed: 36125123
DOI: 10.7554/eLife.78022