Switching constant domains enhances agonist activities of antibodies to a thrombopoietin receptor

Kai, Masayuki; Motoki, Kazuhiro; Yoshida, Hiroyuki; Emuta, Chie; Chisaka, Yukiko; Tsuruhata, Kumi; Endo, Chikara; Muto, Mari; Shimabe, Munetake; Nishiyama, Uichi; Hagiwara, Tetsuya; Matsumoto, Atsushi; Miyazaki, Hiroshi; Kataoka, Satoshi

doi:10.1038/nbt1376

Cited by 25 publications

(21 citation statements)

References 14 publications

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“…Phosphorylation changes in Akt caused by mAb P9 could be due to P9-induced Hsp90 inhibition as shown in Figure 6A. Furthermore, special attention has been recently paid to specific Abs disturbing the hinge-bending movement of the kinase in modulating signaling pathways, including the PI3K/Akt pathway (73). Akt is recruited from the cytosol to the plasma membrane, in which it was phosphorylated at Thr308 and Ser473 by PDK1 in a PI3K-dependent manner (74).…”

Section: Discussionmentioning

confidence: 99%

“…This structure resembles PI3K more closely than it does other protein kinases, although there is little sequence homology between PIM-1 and PI3K (75). Whether specific mAb to PIM-1 could induce conformational changes of the hinge region by using the unique active site of the PIM-1 and inhibit PI3/Akt kinase activity (54,73,75) is the subject for the future studies. Upregulation of the PI3K/Akt pathway is linked to prostate cancer progression (55,56).…”

Section: Discussionmentioning

confidence: 99%

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PIM-1–specific mAb suppresses human and mouse tumor growth by decreasing PIM-1 levels, reducing Akt phosphorylation, and activating apoptosis

Hu¹,

Li²,

Vandervalk³

et al. 2009

J. Clin. Invest.

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Provirus integration site for Moloney murine leukemia virus (PIM1) is a proto-oncogene that encodes a serine/ threonine kinase with multiple cellular functions. Overexpression of PIM-1 plays a critical role in progression of prostatic and hematopoietic malignancies. Here we describe the generation of a mAb specific for GST-PIM-1, which reacted strongly with most human and mouse cancer tissues and cell lines of prostate, breast, and colon origin but only weakly (if at all) with normal tissues. The mAb binds to PIM-1 in the cytosol and nucleus as well as to PIM-1 on the surface of human and murine cancer cells. Treatment of human and mouse prostate cancer cell lines with the PIM-1-specific mAb resulted in disruption of PIM-1/Hsp90 complexes, decreased PIM-1 and Hsp90 levels, reduced Akt phosphorylation at Ser473, reduced phosphorylation of Bad at Ser112 and Ser136, and increased cleavage of caspase-9, an indicator of activation of the mitochondrial cell death pathway. The mAb induced cancer cell apoptosis and synergistically enhanced antitumor activity when used in combination with cisplatin and epirubicin. In tumor models, the PIM-1-specific mAb substantially inhibited growth of the human prostate cancer cell line DU145 in SCID mice and the mouse prostate cancer cell TRAMP-C1 in C57BL/6 mice. These findings are important because they provide what we believe to be the first in vivo evidence that treatment of prostate cancer may be possible by targeting PIM-1 using an Ab-based therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

PIM-1–specific mAb suppresses human and mouse tumor growth by decreasing PIM-1 levels, reducing Akt phosphorylation, and activating apoptosis

Hu¹,

Li²,

Vandervalk³

et al. 2009

J. Clin. Invest.

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“…MA01G4G344, an engineered antibody containing IgG3 and IgG4 parts in addition to an IgG1 variable part, has been shown to be active in vitro [49].…”

Section: Tpo Receptor Agonistic "Antibodies"mentioning

confidence: 99%

Role of growth factors and thrombopoietic agents in the treatment of chronic hepatitis C

Tillmann¹,

Patel²,

McHutchison

2009

Curr Gastroenterol Rep

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Advanced liver disease and interferon-based treatment are both associated with varying degrees of cytopenia in patients with chronic hepatitis C. Growth factors to increase hemoglobin and neutrophils are commonly used in clinical practice, despite the absence of data to indicate benefits in terms of sustained viral response. Thrombocytopenia is observed frequently, is multi-factorial in etiology, and may result in significant limitations on interventional and therapeutic options. A small-molecule thrombopoietin mimetic, eltrombo-pag, has demonstrated a dose-response associated increase in platelet count in a phase 2 study, allowing initiation and completion of a 12-week course of peginterferon plus ribavirin in 36%, 53%, and 65% of patients receiving 30 mg, 50 mg, or 75 mg of eltrombopag daily, respectively, compared with 6% in the placebo arm. Phase 3 studies are currently evaluating whether initiating and maintaining antiviral therapy with eltrombopag will lead to an increase in sustained virologic response in chronic hepatitis C infection.

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“…One of the antibodies, MA01G4344U, has a constant region of human IgG4 and an upper hinge region of human IgG3. 6 MA01G4344U is specific for human MPL and does not cross-react with mouse Mpl. In this study, to evaluate the in vivo efficacy of MA01G4344U in human primary hematopoietic cells, we used a xenotransplanted mouse model.…”

Section: Introductionmentioning

confidence: 99%

“…3-5 Recently we reported the generation of novel anti-MPL agonist antibodies using a human antibody-producing mouse system. 6 We also used subclass switching of the hinge region to improve the agonistic activities of the antibodies. One of the antibodies, MA01G4344U, has a constant region of human IgG4 and an upper hinge region of human IgG3.…”

mentioning

confidence: 99%

In vivo efficacy of anti-MPL agonist antibody in promoting primary human hematopoietic cells

Kai¹,

Hagiwara

Emuta³

et al. 2009

Blood

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In a previous study, we generated novel antithrombopoietin receptor agonist antibodies as therapeutic candidates. In this report, we investigated the in vivo effects of one of these antibodies, MA01G4344U, on primary human hematopoietic cells using xenotransplantation. NOD/Shi-scid, IL-2Rgamma(null) (NOG) mice were pretreated by total-body irradiation and received a transplant of human cord blood-derived CD34(+) cells. Weekly intraperitoneal injection of MA01G4344U (100 microg/mouse per week) or Peg-rhMGDF (5 microg/mouse per week) or phosphate-buffered saline (PBS) was performed. Human cells in peripheral blood were analyzed by flow cytometry and bone marrow cells were analyzed by flow cytometry and colony assay. MA01G4344U successfully increased the number of human CD41(+) platelets and human CD45(+) cells in peripheral blood. In the bone marrow, MA01G4344U increased the number of human CD45(+)/CD34(+) cells, which resulted in more multilineage progenitor cells. The efficacy of MA01G4344U in promoting primary human hematopoietic cells in vivo suggests its therapeutic potential for thrombocytopenic and pancytopenic disorders.

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Switching constant domains enhances agonist activities of antibodies to a thrombopoietin receptor

Cited by 25 publications

References 14 publications

PIM-1–specific mAb suppresses human and mouse tumor growth by decreasing PIM-1 levels, reducing Akt phosphorylation, and activating apoptosis

PIM-1–specific mAb suppresses human and mouse tumor growth by decreasing PIM-1 levels, reducing Akt phosphorylation, and activating apoptosis

Role of growth factors and thrombopoietic agents in the treatment of chronic hepatitis C

In vivo efficacy of anti-MPL agonist antibody in promoting primary human hematopoietic cells

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