Muromonab-CD3 solution for injection 5mg/5ml ampoules

Studies have shown that patients who undergo heart transplantation (HTx) are at an increased risk for developing skin cancer. This condition can add physiological and psychological burden to patients. Therefore, assessing the incidence and identifying risk factors for skin cancer are crucial steps in its prevention. The purpose of this skin study is to systematically evaluate the incidence and risk factors of skin cancer in HTx. Two researchers independently conducted literature searches across 8 databases. The search covered publications from the establishment of the database through October 1, 2024. After screening title, abstract, and the full text, 34 eligible cohort studies were included. The studies were evaluated using the New castle-Ottawa Scale (NOS) for non-randomized studies, and papers selection followed PRISMA guidelines. The meta-analysis was conducted using the Stata 15.0 software. Among 34 cohort studies on HTx, the pooled incidence of skin cancer was 16% (95% CI: 14-19%). The incidences by type were 10% (95% CI: 8-12%) for squamous cell carcinoma and 8% (95% CI: 6-9%) for basal cell carcinoma. Regionally, the highest incidence was observed in the USA 22% (95% CI: 18-27%). Risk factors significantly associated with skin cancer included age (RR: 1.08, 95% CI: 1.04-1.11), male (RR: 1.53, 95% CI:1.11-2.12), white race (RR: 10.23, 95% CI: 7.32-14.30), smoking history (RR:1.26, 95% CI:1.05-1.51), prolonged sunlight exposure (≥ 2500 h) (RR:3.66, 95% CI: 2.11-6.36), pre-transplant cancer (RR: 1.61, 95% CI: 1.43-1.82), muromonab-CD3 (OKT3) (RR: 2.61, 95% CI: 2.11-3.24). The higher incidence of skin cancer observed in this study highlights the urgent need for follow-up care in heart transplant recipients. To address this, tailored skin cancer prevention strategies should be implemented, focusing on modifiable risk factors. Our findings provide a theoretical foundation to help healthcare professionals prevent and manage skin cancer in heart transplant patients.Patient or Public Contribution: YY, and HPY, were responsible for the conception and design of the study. YYS, FYL, and HPY, were responsible for the acquisition, analysis and interpretation of the data. All of the authors drafted the article or revised it critically for important intellectual content and provided final approval of the version to be submitted.

Abstract licence: CC BY-NC-ND

The established protocol for the management of acute myeloid leukemia (AML) has traditionally involved the administration of induction chemotherapy, followed by consolidation chemotherapy, and subsequent allogeneic stem cell transplantation for eligible patients. However, the prognosis for individuals with relapsed and refractory AML remains unfavorable. In response to the necessity for more efficacious therapeutic modalities, targeted immunotherapy has emerged as a promising advancement in AML treatment. This comprehensive review article specifically examines classical unconjugated and toxin-conjugated monoclonal antibodies, which are currently in the preclinical phase or undergoing evaluation in clinical trials. The review delves into the proposed mechanisms through which these monoclonal antibodies elicit anti-tumor activity and identifies the challenges associated with designing targeted immunotherapy. The review focuses on targeting specific antigens in AML, including FLT3/CD125, CLL-1, CD33, CD38, CD47, CD70, and CD123.

Abstract licence: CC BY

Harnessing the immune system to fight cancer has become a reality with the clinical success of immune-checkpoint blockade (ICB) antibodies against PD(L)-1 and CTLA-4. However, not all cancer patients respond to ICB. Thus, there is a need to modulate the immune system through alternative strategies for improving clinical responses to ICB. The CD3-T cell receptor (TCR) is the canonical receptor complex on T cells. It provides the "first signal" that initiates T cell activation and determines the specificity of the immune response. The TCR confers the binding specificity whilst the CD3 subunits facilitate signal transduction necessary for T cell activation. While the mechanisms through which antigen sensing and signal transduction occur in the CD3-TCR complex are still under debate, recent revelations regarding the intricate 3D structure of the CD3-TCR complex might open the possibility of modulating its activity by designing targeted drugs and tools, including aptamers. In this review, we summarize the basis of CD3-TCR complex assembly and survey the clinical and preclinical therapeutic tools available to modulate CD3-TCR function for potentiating cancer immunotherapy.

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B-cell depletion therapy (BCDT) has been employed to treat autoimmune disease for ~20 years. Immunoglobulin G1 (IgG1) monoclonal antibodies targeting CD20 and utilizing effector function (eg, antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis) to eliminate B cells have historically been the predominant therapeutic approaches. More recently, diverse BCDT approaches targeting a variety of B-cell surface antigens have been developed for use in hematologic malignancies, including effector-function-enhanced monoclonal antibodies, chimeric antigen receptor T-cell (CAR-T) treatment, and bispecific T-cell engagers (TCEs). The latter category of antibodies employs CD3 engagement to augment the killing of target cells. Given the improvement in B-cell depletion observed with CAR-T and TCEs compared with conventional monospecific antibodies for treatment of hematologic malignancies and the recent case reports demonstrating therapeutic benefit of CAR-T in autoimmune disease, there is potential for these mechanisms to be effective for B-cell-mediated autoimmune disease. In this review, we discuss the various BCDTs that are being developed in autoimmune diseases, describing the molecule designs, depletion mechanisms, and potential advantages and disadvantages of each approach as they pertain to safety, efficacy, and patient experience. Additionally, recent advances and strategies with TCEs are presented to help broaden understanding of the potential for bispecific antibodies to safely and effectively engage T cells for deep B-cell depletion in autoimmune diseases.

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BackgroundT-cell retargeting to eliminate CEACAM5-expressing cancer cells via CEACAM5xCD3 bispecific antibodies (BsAbs) showed limited clinical activity so far, mostly due to insufficient T-cell activation, dose-limiting toxicities, and formation of anti-drug antibodies (ADA).MethodsWe present here the generation and preclinical development of NILK-2301, a BsAb composed of a common heavy chain and two different light chains, one kappa and one lambda, determining specificity (so-called κλ body format).ResultsNILK-2301 binds CD3ɛ on T-cells with its lambda light chain arm with an affinity of ≈100 nM, and the CEACAM5 A2 domain on tumor cells by its kappa light chain arm with an affinity of ≈5 nM. FcγR-binding is abrogated by the "LALAPA" mutation (Leu234Ala, Leu235Ala, Pro329Ala). NILK-2301 induced T-cell activation, proliferation, cytokine release, and T-cell dependent cellular cytotoxicity of CEACAM5-positive tumor cell lines (5/5 colorectal, 2/2 gastric, 2/2 lung), e.g., SK-CO-1 (Emax = 89%), MKN-45 (Emax = 84%), and H2122 (Emax = 97%), with EC50 ranging from 0.02 to 0.14 nM. NILK-2301 binds neither to CEACAM5-negative or primary colon epithelial cells nor to other CEACAM family members. NILK-2301 alone or in combination with checkpoint inhibition showed activity in organotypic tumor tissue slices and colorectal cancer organoid models. In vivo, NILK-2301 at 10 mg/kg significantly delayed tumor progression in colon- and a pancreatic adenocarcinoma model. Single-dose pharmacokinetics (PK) and tolerability in cynomolgus monkeys at 0.5 or 10 mg/kg intravenously or 20 mg subcutaneously showed dose-proportional PK, bioavailability ≈100%, and a projected half-life in humans of 13.1 days. NILK-2301 was well-tolerated. Data were confirmed in human FcRn TG32 mice.ConclusionsIn summary, NILK-2301 combines promising preclinical activity and safety with lower probability of ADA-generation due to its format compared to other molecules and is scheduled to enter clinical testing at the end of 2023.

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Over 160 therapeutic and in vivo diagnostic monoclonal antibodies have been approved by the US FDA since the first monoclonal antibody, muromonab, was approved in 1986. Approximately 42% of these approvals were for the treatment or in vivo diagnosis of oncology indications, although some products are no longer marketed. This review will look at the history of monoclonal antibody development and approvals, discuss current antibody-based modalities, regulatory considerations for engineering approaches, critical quality attributes for different modalities, immunogenicity of mAbs across oncology products, and the future directions for development of therapeutic and diagnostic monoclonal antibody-based products.

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AbstractT-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Current treatments, based on intensive chemotherapy regimens provide overall survival rates of ∼85% in children and <50% in adults, calling the search of new therapeutic options. We previously reported that targeting the T-cell receptor (TCR) in T-ALL with anti-CD3 (αCD3) monoclonal antibodies (mAbs) enforces a molecular program akin to thymic negative selection, a major developmental checkpoint in normal T-cell development; induces leukemic cell death; and impairs leukemia progression to ultimately improve host survival. However, αCD3 monotherapy resulted in relapse. To find out actionable targets able to re-enforce leukemic cells' vulnerability to αCD3 mAbs, including the clinically relevant teplizumab, we identified the molecular program induced by αCD3 mAbs in patient-derived xenografts derived from T-ALL cases. Using large-scale transcriptomic analysis, we found prominent expression of tumor necrosis factor α (TNFα), lymphotoxin α (LTα), and multiple components of the "TNFα via NF-κB signaling" pathway in anti-CD3-treated T-ALL. We show in vivo that etanercept, a sink for TNFα/LTα, enhances αCD3 antileukemic properties, indicating that TNF/TNF receptor (TNFR) survival pathways interferes with TCR-induced leukemic cell death. However, suppression of TNF-mediated survival and switch to TNFR-mediated cell death through inhibition of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) with the second mitochondrial-derived activator of caspases (SMAC) mimetic birinapant synergizes with αCD3 to impair leukemia expansion in a receptor-interacting serine/threonine-protein kinase 1-dependent manner and improve mice survival. Thus, our results advocate the use of either TNFα/LTα inhibitors, or birinapant/other SMAC mimetics to improve anti-CD3 immunotherapy in T-ALL.

Abstract licence: CC BY-NC-ND