Design of CD40 Agonists and Their Use in Growing B Cells for Cancer Immunotherapy

Kornbluth, Richard S.; Stempniak, M; Stone, Geoffrey W.

doi:10.3109/08830185.2012.703272

Cited by 30 publications

(34 citation statements)

References 65 publications

(61 reference statements)

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“…Crosslinking CP-870,893 or its F(ab)' 2 fragment using a soluble agent did not lead to increased potency of the antibody in our assays whereas crosslinking with CD32-expressing cells led to modest additional upregulation of some but not all activation markers in an Fc-dependent manner. It is well-known that the strength of CD40 signaling via recombinant forms of its natural ligand, CD40L, increases in vitro with increasing crosslinking (26), and thus our results with K32 cells are not particularly surprising. Nevertheless, our results emphasize that CP-870,893 is an active, soluble compound independent of its Fc domain.…”

Section: Resultssupporting

confidence: 52%

Role of Crosslinking for Agonistic CD40 Monoclonal Antibodies as Immune Therapy of Cancer

Richman

Vonderheide

2014

Cancer Immunology Research

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Agonists of the TNF superfamily of receptors hold promise as novel therapy for cancer. Recent data on agonistic anti-murine TNF receptors (TNFR) such as CD40 suggest that the specific engagement of Fc-receptor (FcR) is required for optimal antitumor effects, prompting calls to engineer anti-human CD40 and other TNFR mAb accordingly. CP-870,893 is a fully human anti-CD40 mAb, selected in part because it is an IgG2 which is presumed to have poor reactivity with FcR; however, CP-870,893 has been evaluated in multiple clinical trials with beneficial activity in patients with melanoma, pancreatic and other cancers. Here, we confirmed that the activity of anti-murine CD40 mAb was dependent on FcγRIIB engagement, was decreased significantly in FcγRIIB−/− mice, and upon Fc-crosslinking anti-mouse CD40 mAb enhanced the activation of antigen presenting cells. In contrast, the CP-870,893-mediated activation of human B cells was not enhanced with anti-IgG-crosslinking nor abrogated when used as an F(ab)'2 reagent. Crosslinking of CP-870,893 using the CD32-expressing K562 cells yielded an Fc-dependent modest increase in the expression of some activation markers relative to that of the soluble CP-870,893 mAb. Classic Fc-dependent functions such as antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CMC) were minimal for CP-870,893 as compared to the IgG1 anti-CD20 mAb rituximab, which mediated both ADCC and CMC in parallel assays. Anti-mouse CD40 mAb competed for the CD40 ligand binding site, but CP-870,893 did not. Thus, Fc-crosslinking is not an essential requirement for agonistic anti-human CD40 mAb, whose potency is more dependent on the CD40 epitope recognized and the strength of the signal achieved.

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Section: Resultssupporting

confidence: 52%

Role of Crosslinking for Agonistic CD40 Monoclonal Antibodies as Immune Therapy of Cancer

Richman

Vonderheide

2014

Cancer Immunology Research

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“…The TNF-receptor associated factor TRAF3 is part of the CD40 signaling cascade regulating proliferation, immunoglobulin class switching, and apoptosis (Rousset et al 1991;Tsubata et al 1993;Kornbluth et al 2012). TRAF3 also acts in a complex with TRAF2, BIRC2 (cIAP1), and BIRC3 (cIAP2) to target MAP3K14 (NIK) for degradation, thereby regulating the alternative NF-κB pathway regulating proliferation, B-cell activation, and other processes (for review, see Sun 2011).…”

Section: B-cell Lymphoma Defining Pathways Point To the Importance Ofmentioning

confidence: 99%

Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background

et al. 2015

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Lymphoma is the most common hematological malignancy in developed countries. Outcome is strongly determined by molecular subtype, reflecting a need for new and improved treatment options. Dogs spontaneously develop lymphoma, and the predisposition of certain breeds indicates genetic risk factors. Using the dog breed structure, we selected three lymphoma predisposed breeds developing primarily T-cell (boxer), primarily B-cell (cocker spaniel), and with equal distribution of B-and T-cell lymphoma (golden retriever), respectively. We investigated the somatic mutations in B-and T-cell lymphomas from these breeds by exome sequencing of tumor and normal pairs. Strong similarities were evident between B-cell lymphomas from golden retrievers and cocker spaniels, with recurrent mutations in TRAF3-MAP3K14 (28% of all cases), FBXW7 (25%), and POT1 (17%). The FBXW7 mutations recurrently occur in a specific codon; the corresponding codon is recurrently mutated in human cancer. In contrast, T-cell lymphomas from the predisposed breeds, boxers and golden retrievers, show little overlap in their mutation pattern, sharing only one of their 15 most recurrently mutated genes. Boxers, which develop aggressive T-cell lymphomas, are typically mutated in the PTEN-mTOR pathway. T-cell lymphomas in golden retrievers are often less aggressive, and their tumors typically showed mutations in genes involved in cellular metabolism. We identify genes with known involvement in human lymphoma and leukemia, genes implicated in other human cancers, as well as novel genes that could allow new therapeutic options.

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“…Soon after CD40 and its ligand CD40L (also named CD154) were first described, it became clear that CD40L/CD40 signaling was among the most potent stimuli for the activation of B cells [2, 3]. Classically, CD40L is expressed on activated CD4+ T cells and, thus, is essential for a thymus-dependent B-cell response and for the development of a humoral and cellular immune response.…”

Section: Introductionmentioning

confidence: 99%

B Cell-Based Cancer Immunotherapy

Wennhold

Shimabukuro‐Vornhagen

Bergwelt‐Baildon

2019

Transfus Med Hemother

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B cells are not only producers of antibodies, but also contribute to immune regulation or act as potent antigen-presenting cells. The potential of B cells for cellular therapy is still largely underestimated, despite their multiple diverse effector functions. The CD40L/CD40 signaling pathway is the most potent activator of antigen presentation capacity in B lymphocytes. CD40-activated B cells are potent antigen-presenting cells that induce specific T-cell responses in vitro and in vivo. In preclinical cancer models in mice and dogs, CD40-activated B cell-based cancer immunotherapy was able to induce effective antitumor immunity. So far, there have been only few early-stage clinical studies involving B cell-based cancer vaccines. These trials indicate that B cell-based immunotherapy is generally safe and associated with little toxicity. Furthermore, these studies suggest that B-cell immunotherapy can elicit antitumor T-cell responses. Alongside the recent advances in cellular therapies in general, major obstacles for generation of good manufacturing practice-manufactured B-cell immunotherapies have been overcome. Thus, a first clinical trial involving CD40-activated B cells might be in reach.

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Design of CD40 Agonists and Their Use in Growing B Cells for Cancer Immunotherapy

Cited by 30 publications

References 65 publications

Role of Crosslinking for Agonistic CD40 Monoclonal Antibodies as Immune Therapy of Cancer

Role of Crosslinking for Agonistic CD40 Monoclonal Antibodies as Immune Therapy of Cancer

Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background

B Cell-Based Cancer Immunotherapy

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