4.7 Article

Agonistic CD40 Antibodies and Cancer Therapy

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CLINICAL CANCER RESEARCH
卷 19, 期 5, 页码 1035-1043

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AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-12-2064

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  1. NIH [R01 CA158186, R01 CA169123]
  2. Cancer Research UK
  3. National Centre for the 3Rs
  4. Pfizer
  5. Cancer Research UK [10834] Funding Source: researchfish

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Recent success in cancer immunotherapy has reinvigorated the hypothesis that the immune system can control many if not most cancers, in some cases producing durable responses in a way not seen with many small-molecule drugs. Agonistic CD40 monoclonal antibodies (mAb) offer a new therapeutic option which has the potential to generate anticancer immunity by various mechanisms. CD40 is a TNF receptor superfamily member expressed broadly on antigen-presenting cells (APC) such as dendritic cells, B cells, and monocytes as well as many nonimmune cells and a range of tumors. Agonistic CD40 mAb have been shown to activate APC and promote antitumor T-cell responses and to foster cytotoxic myeloid cells with the potential to control cancer in the absence of T-cell immunity. Thus, agonistic CD40 mAb are fundamentally different from mAb which block negative immune checkpoint such as anti-CTLA-4 or anti-PD-1. Initial clinical trials of agonistic CD40 mAb have shown highly promising results in the absence of disabling toxicity, both in single-agent studies and in combination with chemotherapy; however, numerous questions remain about dose, schedule, route of administration, and formulation. Recent findings about the role played by the IgG isotype and the Fcgamma receptor (Fc gamma R) inmAbcross-linking, together with insights into mechanisms of action, particularly with regard to the role of myeloid cells, are predicted to help design next-generation CD40 agonistic reagents with greater efficacy. Here, we will review the preclinical and clinical data and discuss the major issues facing the field. Clin Cancer Res; 19(5); 1035-43. (C) 2013 AACR.

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