M proteins

T-cell immune responses play a vital role in the control of tumors. To induce robust and durable T-cell immune responses, the initial requirement is a signal induced by T-cell receptor (TCR) activation (Signal 1). Signal 1 is antigen-specific and it is achieved via the interaction between the T-cell receptor and the peptide-major histocompatibility complex (MHC) on the antigen-presenting cell (APC). However, Signal 1 alone is not sufficient to effectively activate T-cell immune responses, and a sufficient co-stimulatory signal (Signal 2) is required. Unlike Signal 1, Signal 2 is not antigen-specific. Signal 2 is achieved through the interaction between the co-stimulatory signal molecules expressed on APCs and T cells. Costimulatory signals are necessary for T-cell proliferation, differentiation, and survival. Without costimulatory signals, there may be an unresponsive/low response T cells, cell death, or the emergence of immune tolerance. Common co-stimulatory molecule protein families include the IgSF (Immunoglobulin Superfamily), TNRSF (Tumor Necrosis Factor Receptor Superfamily), in addition to others derived from the TIM family, CD2/SLAM family of costimulatory factors. Due to the critical role of costimulatory factors in T-cell immune activation, they have been of particular interest in the field of tumor therapy. 4-1BB4-1BB (also known as CD137 or TNFRSF9) was first discovered in 1989 and is a critical co-stimulation receptor on T cells and other immune cells. It is a member of the TNRSF protein family mentioned earlier. In 1997, Melero and colleagues found that a monoclonal antibody against 4-1BB was able to induce anti-tumour activity in T cells in mice. The main effects of 4-1BB on T cell activation include cell proliferation, cytokine release, cytotoxicity, and the formation of long-term immune memory, among others. Most of T cell activation occurs in CD8+ T cells. Two second-generation CAR-T cell therapies, Kymriah (Novartis) and CARVYKTI (Johnson&Johnson), which have been approved by the FDA, utilise 4-1BB as their co-stimulation domain. Other second-generation CAR-T therapies use CD28 as their co-stimulatory domain. Although both have shown similar tumour control rates in cancer patients, some differences were found: CD28 appears to have a higher cytokine release effect and can better promote T cell proliferation, but it also has a higher risk of neurotoxicity, while 4-1BB can foster longer-term T cell persistence. 👇Please click on the picture link below for free registration or login directly if you have freemium accounts, you can browse the latest research progress on drugs, indications, organizations, clinical trials, clinical results, and drug patents related to this target. 4-1BB is a glycosylated type-I membrane protein. It has four functional domains (known as "CRD", cysteine-rich pseudo repeats domain). The 4-1BB ligand (4-1BBL) is the binding partner of 4-1BB, which is generally expressed on the cell surface as a homotrimeric complex. Upon antigen stimulation, effective binding between 4-1BB and 4-1BBL can activate rapid receptor activation. For optimal co-stimulation (signal 2), 4-1BB needs to cluster on the cell surface. The Application of 4-1BB in Antibody Drug DevelopmentThe First Generation of 4-1BB Agonist Drugs The clinical development of 4-1BB agonist antibodies began in 2005 with the antibody drug urelumab (BMS-663513) created by Bristol-Myers Squibb (BMS). Urelumab is a humanized anti-4-1BB IgG4 subtype antibody. The early development data was promising, but there were two serious adverse events due to hepatic toxicity. Subsequent research found that while the drug was effective, its potency was very limited when administered at a safe dose (0.1 mg/kg). The second 4-1BB antibody drug developed was Pfizer's utomilumab (PF-05082566). The antibody drug is a fully human IgG2 subtype antibody and entered clinical trials in 2011. Although it did not demonstrate the safety issues seen in urelumab, its effectiveness (whether used alone or in combination with rituximab) was very limited, leading to the discontinuation of its clinical development. Urelumab and utomilumab, as the first generation of 4-1BB antibodies, displayed different agonistic activities and liver toxicities. These differences are currently thought to be due to differences in the Fc effector functions and epitope binding of these two molecules. The Fc effector function, particularly binding to FcγRIIB, is generally believed to be associated with liver toxicity (FcγRIIB cross-linking in the liver). As an IgG4 subtype, urelumab has stronger FcγRIIB binding, which is likely why it differs in liver toxicity from utomilumab (IgG2 subtype). The epitope binding is another reason for the different activities between urelumab and utomilumab. Urelumab and 4-1BB bind through an epitope on CRD1, which does not interfere with the binding of 4-1BB to its natural ligand. Utomilumab binds to 4-1BB through epitopes on CRD2 and CRD3. This binding method results in a large amount of endogenous 4-1BB ligand competing with utomilumab for binding to the 4-1BB receptor, limiting the activity of 4-1BB receptor clustering (which promotes the agonist activity of 4-1BB). This explains why urelumab (which does not affect 4-1BB receptor clustering) has higher agonist activity than utomilumab (which does affect 4-1BB receptor clustering). Second Generation 4-1BB Agonist Drugs The mediocre performance of Urelumab and Utomilumab in clinical trials did not douse the interest of many pharmaceutical companies in further exploring the 4-1BB target. Since the beginning of 2017 to the present, more than 40 4-1BB agonist drugs have entered clinical trials. Although the clinical trials of 4-1BB drugs temporarily declined in 2020 due to the COVID-19 pandemic, they showed a strong rebound afterwards. There may be more and more 4-1BB agonist drugs entering the clinic in the future, as many pharmaceutical/biotech companies are actively conducting preclinical research on 4-1BB drugs. The 4-1BB drugs that appeared after Urelumab and Utomilumab are categorized as the second-generation 4-1BB agonist drugs in this article. The second-generation 4-1BB agonist drugs mainly fall into two categories: IgG type (mono-antibody structure) and bi/multi-antibody 4-1BB agonist drugs. The mechanism of action of the IgG type second-generation 4-1BB agonist drugs has some consistency with the first-generation drugs (Urelumab and Utomilumab): they mostly rely on the cross-linking effect of Fcγ receptors, but their binding epitopes have been modified compared to the first generation. For example, the drug ADG106 developed by Suzhou Tyvance Biotech, also adopts the IgG4 subtype like Urelumab, but it does not bind to Urelumab's epitope CRD1. The concept behind this design is to have the drug be effective while reducing its toxic side effects, achieving a more precise regulation of the balance between effectiveness and safety (“sweet point” of functionality). The second type of second-generation 4-1BB agonist drugs are bi/multi-antibody agonist drugs. These drugs bind to at least one other target in addition to 4-1BB. Adding another target can increase the specificity of the drug, its cross-linking effect, and confer additional stimulatory or inhibitory activity, endowing the drug with extra anti-tumor properties. Targets commonly paired with 4-1BB include: PD-L1 (e.g., I-MAB Biopharma's TJ-L14B, Nanjing Leads Biolabs's LBL-024, Biotheus' PM1003), FAP (e.g., Roche's RG7827, Boehringer Ingelheim's BI765179) etc. In addition, the Fc end of this type of drug has been engineered to eliminate the ability to bind with Fcγ receptors but maintain the ability to bind with neonatal Fc receptors (FcRn) to ensure the half-life of the drug in the body. The aim is to suppress the liver toxicity seen in Urelumab, improving the safety of the drug. Drugs adopting this design strategy include Roche's RG7827 and RG6076, Elpiscience Biopharma's ES101, I-MAB Biopharma's TJ-L14B etc. Immunotherapy, surgery, radiation therapy, and chemotherapy together constitute the four methods of cancer treatment. In order to enhance the efficacy, surgery/chemotherapy/radiation therapy can be combined with immunotherapy as a joint treatment strategy. Currently, the combination of 4-1BB with radiation therapy and chemotherapy has been shown to have a good synergistic effect. In addition, anti-4-1BB antibodies have also been shown to improve the efficacy of other antibodies. Joint treatment plans based on 4-1BB antibodies may be a direction for future advancements in cancer treatment.

OEGSTGEEST, The Netherlands, April 27, 2023 /PRNewswire/ -- ISA Pharmaceuticals, B.V., a clinical stage biotech company developing immunotherapies to treat cancers and infectious diseases, is pleased to announce that it will be presenting data evaluating the response to its T cell inducing SLP therapy against SARS-CoV-2 in collaboration with the Leiden University Medical Center (LUMC) and Centre for Human Drug Research (CHDR) at the 20th Annual Meeting of the Association for Cancer Immunotherapy (CIMT), being held in Mainz, Germany on 3-5 May, 2023. Details of the presentation are as follows: Presentation title: T cell inducing SLP vaccine against SARS-CoV-2 for protection of patients with spontaneous or therapy-induced B cell deficiencies Session: Therapeutic Vaccination, New Targets New Leads, Tumor Biology & Interaction with the Immune System Abstract Number: 167 Presenting Author: Esmé TI van der Gracht Date & Time: Thursday, 4 May at 3:30 pm - 6:00 pm CEST Abstracts are published and can be accessed on the CIMT website at ISA's versatile synthetic long peptide (SLP®) immunotherapy platform is designed to elicit a strong and specific T cell immune response against a target, with the intention to clear an established infection. ISA106, a SARS-CoV-2 immunotherapeutic, consists of multiple SLPs derived from the S, N and M proteins, carefully designed for optimal immunogenicity, administration and manufacturability. The presentation entitled 'T cell inducing SLP vaccine against SARS-CoV-2 for protection of patients with spontaneous or therapy-induced B cell deficiencies' demonstrates that ISA106 adjuvanted SLP therapy is capable of eliciting robust T cell responses in mice and reactivating robust memory T cell responses. These are demonstrable ex vivo in peripheral blood mononuclear cells (PBMCs) from convalescent donors who recovered from SARS-CoV-2 infection. The data confirms that further development of ISA106 is warranted to provide improved protection against SARS-CoV-2 virus-induced disease, in persons with spontaneous or therapy-induced B cell deficiencies, by inducing adequate anti-viral T cell immunity. These data further demonstrate the power of ISA's SLP platform to activate the immune system and generate strong and broad T-cell responses against specific targets of interest. Dr Esmé TI van der Gracht, Immunology Scientist at ISA Therapeutics, said: "We are delighted to be sharing data demonstrating the progress we are making with our SLP therapy targeting the highly transmissible and pathogenic SARS-CoV-2. The data support further development of ISA106 for the protection of immunocompromised people for whom currently approved SARS-CoV-2 vaccines are insufficiently protective." If you would like to meet with ISA Pharmaceuticals at the above event, please contact us at [email protected]. For more information, please visit us at isa-pharma.com. About ISA Pharmaceuticals ISA Pharmaceuticals is an immunotherapy company developing treatments for various cancers and infectious diseases. ISA has best-in-class technology to stimulate and activate the human immune system, specifically T cells, to fight diseased or infected cells. Its lead asset ISA101b is in late-stage clinical trials for human papillomavirus type 16 (HPV16)-induced cancers in a collaboration with biotechnology company Regeneron. Other assets are in preclinical stage development and include immunotherapies to treat patients that suffer from cancers that over-express PRAME, chronic hepatitis B or SARS-CoV2 infections. For more information, please visit . About CIMT The Association for Cancer Immunotherapy CIMT is a member-based information and education platform that facilitates the knowledge exchange between academic and industry scientists, physicians and regulatory authorities who research and develop cancer immunotherapies. Since 2003, the CIMT Annual Meeting has connected the global cancer immunotherapy community in the heart of Europe. As the largest science-driven, not-for-profit event in Europe on cancer immunology and immunotherapy, CIMT invites international participants for high-level scientific exchange, collaboration and discussion focused on cancer immunotherapy. For more information on the Association for Cancer Immunotherapy, please go to SOURCE ISA Pharmaceuticals

A new study confirms that idiopathic plasmacytic lymphadenopathy is an independent disease subtype of idiopathic multicentric Castleman disease. Idiopathic plasmacytic lymphadenopathy (IPL) is a clinical condition marked by an excessive amount of antibody production due to the proliferation of polyclonal plasma cells in the lymph nodes. At present, it is not clear if IPL is a subtype of idiopathic multicentric Castleman disease (iMCD)-not otherwise specified (NOS). In a new study, researchers from Okayama University have found clinicopathological evidence needed to establish a separate disease unit for IPL under iMCD-NOS. Multicentric Castleman disease (MCD) comprises a heterogenous group of rare disorders that exhibit generalized symptoms such as swelling of lymph nodes, anemia, fever, and fatigue. The causative factors underlying MCD include Kaposi sarcoma-associated herpesvirus (KSHV)/ human herpesvirus 8 (HHV8) infections. KSHV/HHV8-negative MCD without association with the POEMS (polyneuropathy, organomegaly, endocrinopathy, M proteins, and skin changes) syndrome are termed "idiopathic," i.e., diseases with no identifiable cause, and are thus referred to as "iMCD." At present, specific clinical manifestations or diagnostic criteria have not been identified for iMCD, which often results in treatment delay. iMCD is further classified as iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) and iMCD-NOS (not otherwise specified). With additional research efforts, iMCD-NOS, which is highly heterogenous, could be classified into various subtypes. Interestingly, a disease known as idiopathic plasmacytic lymphadenopathy (IPL), which is characterized by hypergammaglobulinemia, i.e., high levels of serum immunoglobulins, and histologically mature plasma cell proliferation in the lymph nodes, is considered a part of iMCD-NOS due to their clinicopathological similarity. However, till date, no study has validated if IPL has distinct clinicopathologic features compared to other iMCD-NOS. This motivated a team of researchers led by Assistant Professor Asami Nishikori, including Associate Professor Midori Filiz Nishimura, and Professor Yasuharu Sato from Department of Molecular Hematopathology, Okayama University Graduate School of Health Sciences, Japan to conduct a thorough clinicopathological examination of IPL and others in iMCD. Their findings were published on September 7, 2022, in the International Journal of Molecular Sciences. "We wanted to determine whether IPL has distinct and uniform clinicopathologic features compared to other subtypes (non-IPL) in iMCD-NOS," remarks Assist. Prof. Nishikori while discussing the motivation behind the study. The team analyzed lymph node specimens derived from 42 Japanese patients with lymph node involvement of iMCD-NOS, who met the consensus diagnostic criteria of iMCD and were negative for KSHV/HHV8 infections. Upon further examination, the team classified 34 of the 42 patients as the IPL group and the remaining 8 as the non-IPL group. On grading histological features such as vascularity, plasmacytosis (high proportion of plasma cells), atrophic and hyperplastic germinal centers (GCs), the team identified significant pathological differences between the specimens of the IPL and non-IPL groups. The IPL group demonstrated greater plasmacytosis and hyperplastic GCs compared to the non-IPL group. Conversely, the vascularity of the non-IPL group was higher than that of the IPL group. Clinically, the IPL group exhibited higher platelet count and serum antibody (immunoglobulin G) levels, with lesser fluid retention in pleural and/or abdominal cavity. The frequency of disease-specific autoantibody detection was also different between the groups. In addition, the clinical course and treatment responses in the two groups were also distinct. Upon treatment with tocilizumab, an anti-interleukin 6 receptor monoclonal antibody approved to treat iMCD in Japan, there was a significant improvement in the condition of patients with IPL. In contrast, patients with non-IPL responded poorly to the drug and showed progressed disease activity, requiring more intensive treatment. These findings were consistent with those of previous studies that suggest that the clinical course of IPL disease progression is slower as compared to the non-IPL group, and with a superior response to anti-IL-6 agents. Discussing these findings, Assist. Prof. Nishikori states "Given the heterogeneity of non-IPL cases, we must try to identify its primary cause. Molecular analysis could lead to a better understanding of disease pathology and the development of subsequent targeted therapies." To sum up, these findings have established IPL as a clinicopathologically uniform disease, which can be reclassified into an independent subtype of iMCD. So, what are the future implications of these findings? "It is critical that patients get the most out of any treatment modules. Studies on iMCD subtype-specific diagnostic biomarkers, treatment, and follow-up are thus warranted in the future to improve the clinical outcomes for these patients," concludes Assist. Prof. Nishikori.