Transient Removal of CD46 Is Safe and Increases B-cell Depletion by Rituximab in CD46 Transgenic Mice and Macaques

Beyer, Ines; Cao, Hua; Persson, Jonas; Wang, Hongjie; Liu, Ying; Yumul, Roma; Li, Zongyi; Woodle, D.; Manger, R; Gough, Michael; Rocha, Diane; Bogue, Jaclyn; Baldessari, Audrey; Berenson, Ronald J.; Carter, Darrick; Lieber, André

doi:10.1038/mt.2012.212

Cited by 19 publications

(32 citation statements)

References 42 publications

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“…Recently, the removal of CD46 by the application of a small recombinant protein causing its internalization enhanced efficacy of rituximab, alemtuzumab and trastuzumab, and was safe in a mouse and macaque model. 77 Expression of mCRPs is modulated by cytokines. 78 For example, IL-1b downregulated the expression of CD46 and CD59, whereas IL-4 only affected CD46 expression.…”

Section: Inhibition Of Complement Regulatorsmentioning

confidence: 99%

Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer

Meyer

Leusen

Boross

2014

mAbs

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Section: Inhibition Of Complement Regulatorsmentioning

confidence: 99%

Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer

Meyer

Leusen

Boross

2014

mAbs

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“…For example, Ad35K++ promotes killing of several lymphoma cell lines by rituximab, a humanized IgG1 targeting CD20 . Moreover, in vivo administration of Ad35K++ to non‐human primates, that ubiquitously express CD46, appears to be safe and well tolerated . Therefore, using recombinant proteins targeting CD46 may be of potential use in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Recombinant Ad35 adenoviral proteins as potent modulators of human T‐cell activation

et al. 2015

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SummaryThe protein CD46 protects cells from complement attack by regulating cleavage of C3b and C3d. CD46 also regulates the adaptive immune response by controlling T-cell activation and differentiation. Co-engagement of the T-cell receptor and CD46 notably drives T-cell differentiation by switching production of interferon-c to secretion of anti-inflammatory interleukin-10. This regulatory pathway is altered in several chronic inflammatory diseases, highlighting its key role for immune homeostasis. The manipulation of the CD46 pathway may therefore provide a powerful means to regulate immune responses. Herein, we investigated the effect of recombinant proteins derived from the fibre knob of the adenovirus serotype 35 (Ad35) that uses CD46 as its entry receptor, on human T-cell activation. We compared the effects of Ad35K++, engineered to exhibit enhanced affinity to CD46, and of Ad35KÀ, mutated in the binding site for CD46. Ad35K++ profoundly affects T-cell activation by decreasing the levels of CD46 at the surface of primary T cells, and impairing T-cell coactivation, shown by decreased CD25 expression, reduced proliferation and lower secretion of interleukin-10 and interferon-c. In contrast, Ad35KÀ acts a potent co-activator of T cells, enhancing T-cell proliferation and cytokine production. These data show that recombinant Ad35 proteins are potent modulators of human T-cell activation, and support their further development as potential drugs targeting T-cell responses.

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“…Cytolysis assays were performed using trypan blue exclusion assays, which have been used in many previous studies and are still widely used today (2,20,26,42,45,58,65). Briefly, cells in the logarithmic growth phase were released from the culture flask using 3 mM EDTA and were washed.…”

Section: Methodsmentioning

confidence: 99%

CD55 limits sensitivity to complement-dependent cytolysis triggered by heterologous expression of α-gal xenoantigen in colon tumor cells

Wang

Qin

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Y. CD55 limits sensitivity to complement-dependent cytolysis triggered by heterologous expression of ␣-gal xenoantigen in colon tumor cells. Am J Physiol Gastrointest Liver Physiol 306: G1056-G1064, 2014. First published April 24, 2014 doi:10.1152/ajpgi.00464.2013.-Engineering cancer cells to express heterologous antigen ␣-gal and induce the destruction of tumor cells depending on the complement cascade may be a promising strategy of tumor therapy. However, the feasibility and effect of using ␣-gal to induce colorectal adenocarcinoma cell line cytolysis is not yet known. In this study, we evaluated ␣-gal expression's ability to sensitize human colorectal adenocarcinoma cell lines to complement attack in cell lines LoVo, SW620, and Ls-174T. Nearly all ␣-gal-expressing LoVo and SW620 cells were killed by normal human serum (NHS), but ␣-gal-expressing Ls-174T cells showed no significant lysis. We analyzed the expression levels of membrane-bound complement regulatory proteins (mCRPs) on the three cell lines, and their protective role in ␣-gal-mediated activation of the complement. LoVo showed no expression of any of the three proteins. CD59 was strongly expressed by SW620 and Ls-174T. CD46 and CD55 varied between the two cell lines. CD46 on SW620 was only half the intensity of CD46 on Ls-174T. Ls-174T showed a notable expression of CD55, while expression of CD55 on SW620 was not detected. The sensitivity of Ls-174T expressing ␣-gal to NHS greatly increased following the downregulation of CD46 and CD55 with short hairpin RNA (shRNA). However, there is no increase in cell killing when CD59 expression was diminished. Our findings suggest that the use of ␣-gal as antigen to induce tumor cell killing may be a potential therapeutic strategy in colon cancer and that CD55 plays a primary role in conferring resistance to lysis. ␣-gal epitope; membrane-bound complement regulatory proteins; complement-dependent cytotoxicity; colorectal carcinoma COLORECTAL CANCER is the third most commonly diagnosed cancer in males and the second in females (28, 57). Surgery is the mainstay of treatment in most cases of colon cancer. Adjuvant therapies, primarily chemotherapy and radiotherapy, have improved the survival rate and quality of life in colorectal cancer patients. However, the 5-yr survival rate remains at ϳ50%, which explains the growing interest in alternative therapies that have no serious side effects and that have the potential to eradicate residual tumors after conventional treatment. A deeper understanding of the interaction between the host immune system and malignant tumors has enabled the development of effective clinical strategies that improve immune responses against tumors. We seek to develop a therapeutic strategy that induces a specific immune response resulting in direct tumor cell killing, depending on the activation of the complement system.

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Transient Removal of CD46 Is Safe and Increases B-cell Depletion by Rituximab in CD46 Transgenic Mice and Macaques

Cited by 19 publications

References 42 publications

Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer

Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer

Recombinant Ad35 adenoviral proteins as potent modulators of human T‐cell activation

CD55 limits sensitivity to complement-dependent cytolysis triggered by heterologous expression of α-gal xenoantigen in colon tumor cells

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