The Use of Agonistic Anti-CD40 Therapy in Treatments for Cancer

Khong, Andrea; Nelson, Delia J.; Nowak, Anna K.; Lake, Richard; Robinson, Bruce

doi:10.3109/08830185.2012.698338

Cited by 67 publications

(66 citation statements)

References 117 publications

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“…Preclinically, anti-CD40 mAb has been combined with many other approaches, including surgery, chemotherapy, cytokines (IL-2 or IL-15), Toll-like receptor stimulation, anti-CTLA-4, anti-CD137, and adoptive T-cell therapy (reviewed in ref. 24). Of these combination approaches with agonistic anti-CD40 mAb, clinical trials have focused on various chemotherapies (e.g., gemcitabine, cisplatin and pemetrexed, paclitaxel, and carboplatin).…”

Section: Discussionmentioning

confidence: 99%

Combined Anti-CD40 and Anti–IL-23 Monoclonal Antibody Therapy Effectively Suppresses Tumor Growth and Metastases

et al. 2014

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Tumor-induced immunosuppression remains one of the major obstacles to many potentially effective cancer therapies and vaccines. Host interleukin (IL)-23 suppresses the immune response during tumor initiation, growth, and metastases, and neutralization of IL-23 causes IL-12-dependent antitumor effects. Here, we report that combining agonistic anti-CD40 monoclonal antibodies (mAb) to drive IL-12 production and anti-IL-23 mAbs to counter the tumor promoting effects of IL-23 has greater antitumor activity than either agent alone. This increased antitumor efficacy was observed in several experimental and spontaneous lung metastases models as well as in models of de novo carcinogenesis. The combination effects were dependent on host IL-12, perforin, IFNg, natural killer, and/or T cells and independent of host B cells and IFN-ab sensitivity. Interestingly, in the experimental lung metastases tumor models, we observed that intracellular IL-23 production was specifically restricted to MHC-II hi CD11c þ CD11b þ cells. Furthermore, an increase in proportion of these IL-23-producing cells was detected only in tumor models where IL-23 neutralization was therapeutic. Overall, these data suggest the clinical potential of using anti-CD40 (push) and anti-IL-23 mAbs (pull) to tip the IL-12/23 balance in established tumors. Cancer Res; 74(9); 2412-21. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Combined Anti-CD40 and Anti–IL-23 Monoclonal Antibody Therapy Effectively Suppresses Tumor Growth and Metastases

et al. 2014

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“…Agonistic rat-anti-mouse CD40 (clone: FGK4.5) and rat IgG2a (clone: 2A3) were purchased from Bio X Cell. The hCD40 þ Raji cell line was cultured in R10 medium (RPMI-1640 supplemented with L-glutamine and 10% FBS), at 37 C and 5% CO 2 . The human EJ bladder cancer cell line (21) was cultured in R10 medium supplemented with 100 U/mL penicillin-streptomycin at 37 C and 5% CO 2 …”

Section: Antibodies and Cell Linesmentioning

confidence: 99%

“…Several clinical trials have been reported for agonistic CD40 antibodies (2,8), including CP-870,893 (IgG2; ref. 9), ChiLob 7/4 (10), and SGN-40 (IgG1), the latter being a weak CD40 agonist (11).…”

Section: Introductionmentioning

confidence: 99%

“…It is expressed on a variety of immune cells, such as B cells, dendritic cells (DC), monocytes, and macrophages, but also on several tumors, such as B cell lymphomas and carcinomas (1). CD40 agonists trigger effective antitumor responses in preclinical models (2,3). These responses occur via two distinct mechanisms: (i) tumor-specific immune responses, and (ii) direct tumoricidal effects such as apoptosis and antibodydependent cellular cytotoxicity (ADCC; ref.…”

Section: Introductionmentioning

confidence: 99%

“…These responses occur via two distinct mechanisms: (i) tumor-specific immune responses, and (ii) direct tumoricidal effects such as apoptosis and antibodydependent cellular cytotoxicity (ADCC; ref. 2). The indirect antitumor immune effect, which is independent of the CD40 status of the tumor, is mediated by tumor-specific cytotoxic T lymphocytes (4)(5)(6), and possibly macrophages in certain tumor types (7).…”

Section: Introductionmentioning

confidence: 99%

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The Human Agonistic CD40 Antibody ADC-1013 Eradicates Bladder Tumors and Generates T-cell–Dependent Tumor Immunity

Mangsbo

Broos

Fletcher

et al. 2015

Clinical Cancer Research

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Purpose: Local administration of immune-activating antibodies may increase the efficacy and reduce the immune-related adverse events associated with systemic immunotherapy of cancer. Here, we report the development and affinity maturation of a fully human agonistic CD40 antibody (IgG1), ADC-1013.Experimental Design: We have used molecular engineering to generate an agonistic antibody with high affinity for CD40. The functional activity of ADC-1013 was investigated in human and murine in vitro models. The in vivo effect was investigated in two separate bladder cancer models, both using human xenograft tumors in immune deficient NSG mice and using a syngeneic bladder cancer model in a novel human CD40 transgenic mouse.Results: Activation of dendritic cells (DC) by ADC-1013 results in upregulation of the costimulatory molecules CD80 and CD86, and secretion of IL12. ADC-1013 also activates DCs from human CD40 transgenic mice, and peptide-pulsed and ADC-1013-stimulated DCs induce antigen-specific T-cell proliferation in vitro. In vivo, treatment with ADC-1013 in a syngeneic bladder cancer model, negative for hCD40, induces significant antitumor effects and long-term tumor-specific immunity. Furthermore, ADC-1013 demonstrates significant antitumor effects in a human bladder cancer transplanted into immunodeficient NSG mice.Conclusions: Our data demonstrate that ADC-1013 induces long-lasting antitumor responses and immunologic memory mediated by CD40 stimulation. To the best of our knowledge, ADC-1013 represents the first immunomodulatory antibody developed for local immunotherapy of cancer.

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Engineered Bifunctional Proteins for Targeted Cancer Therapy: Prospects and Challenges

Xu²

2021

Advanced Materials

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Bifunctional proteins (BFPs) are a class of therapeutic agents produced through genetic engineering and protein engineering, and are increasingly used to treat various human diseases, including cancer. These proteins usually have two or more biological functions—specifically recognizing different molecular targets to regulate the related signaling pathways, or mediating effector molecules/cells to kill tumor cells. Unlike conventional small‐molecule or single‐target drugs, BFPs possess stronger biological activity but lower systemic toxicity. Hence, BFPs are considered to offer many benefits for the treatment of heterogeneous tumors. In this review, the authors briefly describe the unique structural feature of BFP molecules and innovatively divide them into bispecific antibodies, cytokine‐based BFPs (immunocytokines), and protein toxin‐based BFPs (immunotoxins) according to their mode of action. In addition, the latest advances in the development of BFPs are discussed and the potential limitations or problems in clinical applications are outlined. Taken together, future studies need to be centered on understanding the characteristics of BFPs for optimizing and designing more effective such drugs.

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The Use of Agonistic Anti-CD40 Therapy in Treatments for Cancer

Cited by 67 publications

References 117 publications

Combined Anti-CD40 and Anti–IL-23 Monoclonal Antibody Therapy Effectively Suppresses Tumor Growth and Metastases

Combined Anti-CD40 and Anti–IL-23 Monoclonal Antibody Therapy Effectively Suppresses Tumor Growth and Metastases

The Human Agonistic CD40 Antibody ADC-1013 Eradicates Bladder Tumors and Generates T-cell–Dependent Tumor Immunity

Engineered Bifunctional Proteins for Targeted Cancer Therapy: Prospects and Challenges

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