Apoptosis inducing bivalent single-chain antibody fragments against CD47 showed antitumor potency for multiple myeloma

Kikuchi, Yasufumi; Uno, Shinsuke; Kinoshita, Yasuko; Yoshimura, Yasushi; Iida, Shinichiro; Wakahara, Yuji; Tsuchiya, Masayuki; Yamada-Okabe, Hisafumi; Fukushima, Naoshi

doi:10.1016/j.leukres.2004.09.005

Cited by 63 publications

(55 citation statements)

References 19 publications

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“…Consistent with previous reports, 12,13,15,25 B6H12 induced the phagocytosis of myeloma cells but a non-blocking anti-CD47 antibody, clone 2D3, showed minimal increase of the phagocytosis (Supplementary Figure S2). Previously, it was reported that bivalent single-chain antibodies targeting CD47 induced the apoptosis of leukemia, 31 myeloma, 26 monocytes and dendritic cells. 32 However, B6H12 itself did not have cytotoxicity to myeloma cells (Supplementary Figure S3).…”

Section: Discussionmentioning

confidence: 99%

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Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells

et al. 2012

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Multiple myeloma is a plasma cell neoplasm residing in bone marrow. Despite advances in myeloma therapies, novel therapies are required to improve patient outcomes. CD47 is highly expressed on myeloma cells and a potential therapeutic candidate for myeloma therapies. Flow cytometric analysis of patient bone marrow cells revealed that myeloma cells overexpress CD47 when compared with non-myeloma cells in 73% of patients (27/37). CD47 expression protects cells from phagocytosis by transmitting an inhibitory signal to macrophages. Here we show that blocking CD47 with an anti-CD47 monoclonal antibody increased phagocytosis of myeloma cells in vitro. In xenotransplantation models, anti-CD47 antibodies inhibited the growth of RPMI 8226 myeloma cells and led to tumor regression (42/57 mice), implicating the eradication of myeloma-initiating cells. Moreover, anti-CD47 antibodies retarded the growth of patient myeloma cells and alleviated bone resorption in human bone-bearing mice. Irradiation of mice before myeloma cell xenotransplantation abolished the therapeutic efficacy of anti-CD47 antibodies delivered 2 weeks after radiation, and coincided with a reduction of myelomonocytic cells in spleen, bone marrow and liver. These results are consistent with the hypothesis that anti-CD47 blocking antibodies inhibit myeloma growth, in part, by increasing phagocytosis of myeloma cells.

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Section: Discussionmentioning

confidence: 99%

“…26 We examined whether anti-CD47 antibodies (B6H12) affected the viability of myeloma cells. Neither 10 nor 50 mg/ml of B6H12 affected the viability of RPMI 8226 and NCI H929 myeloma cells after 24-48 h incubation (Supplementary Figure S3A).…”

Section: Patient Myeloma Cells Express High Levels Of Cd47mentioning

confidence: 99%

Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells

et al. 2012

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“…Antibodies directed against CD47 have also been shown to directly induce apoptosis of several hematopoietic malignancies (30)(31)(32). We therefore incubated sphere-derived cells with anti-hCD47 mAb B6H12.2, but in the absence of macrophages, and subsequently assessed apoptosis 2 and 12 hours after treatment by Annexin V staining.…”

Section: Anti-cd47 Treatment Induces Apoptosis Of Pancreatic Cscsmentioning

confidence: 99%

Inhibition of CD47 Effectively Targets Pancreatic Cancer Stem Cells via Dual Mechanisms

Cioffi

Trabulo

Hidalgo

et al. 2015

Clinical Cancer Research

187

148

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Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a cancer of the exocrine pancreas with unmet medical need and is strongly promoted by tumor-associated macrophages (TAM). The presence of TAMs is associated with poor clinical outcome, and their overall role, therefore, appears to be protumorigenic. The “don't eat me” signal CD47 on cancer cells communicates to the signal regulatory protein-α on macrophages and prevents their phagocytosis. Thus, inhibition of CD47 may offer a new opportunity to turn TAMs against PDAC cells, including cancer stem cells (CSC), as the exclusively tumorigenic population. Experimental Design: We studied in vitro and in vivo the effects of CD47 inhibition on CSCs using a large set of primary pancreatic cancer (stem) cells as well as xenografts of primary human PDAC tissue. Results: CD47 was highly expressed on CSCs, but not on other nonmalignant cells in the pancreas. Targeting CD47 efficiently enhanced phagocytosis of a representative set of primary human pancreatic cancer (stem) cells and, even more intriguingly, also directly induced their apoptosis in the absence of macrophages during long-term inhibition of CD47. In patient-derived xenograft models, CD47 targeting alone did not result in relevant slowing of tumor growth, but the addition of gemcitabine or Abraxane resulted in sustained tumor regression and prevention of disease relapse long after discontinuation of treatment. Conclusions: These data are consistent with efficient in vivo targeting of CSCs, and strongly suggest that CD47 inhibition could be a novel adjuvant treatment strategy for PDAC independent of underlying and highly variable driver mutations. Clin Cancer Res; 21(10); 2325–37. ©2015 AACR.

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“…1 Ligation of CD47 is known to induce apoptotic and nonapoptotic death in several cell types including activated T cells, 39 B-cell chronic lymphocytic leukemia, 40,41 promyelocytic leukemia, 42 multiple myeloma, 43 breast carcinoma, 44 and monocytes and dendritic cells. 45 Jurkat T cells deficient of CD47 are resistant to Fas-mediated cell death and are sensitized to death by ligation of Fas and re-expression of CD47.…”

Section: ) (D) Wt Cd47mentioning

confidence: 99%

CD47 deficiency confers cell and tissue radioprotection by activation of autophagy

et al. 2012

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Apoptosis inducing bivalent single-chain antibody fragments against CD47 showed antitumor potency for multiple myeloma

Cited by 63 publications

References 19 publications

Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells

Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells

Inhibition of CD47 Effectively Targets Pancreatic Cancer Stem Cells via Dual Mechanisms

CD47 deficiency confers cell and tissue radioprotection by activation of autophagy

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