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Impact on N-Glycosylation profile of monoclonal anti-D antibodies as a way to control their immunoregulatory and cytotoxic properties

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Abstract

Prophylaxis of hemolytic disease of newborns is based on the ability of polyclonal anti-D antibodies for sup-pressing maternal immune response against D-positive fetal red blood cells. The immunosuppressive effect of anti-D antibody is mediated by interaction between its Fc-fragment and low-affinity IgG Fc-receptor (FcγR) on the immune cell. No clinically effective monoclonal anti-D antibody (mAb) that can replace polyclonal anti-D immunoglobulin has been developed yet. The goals of this study were comparison of structural and functional properties of human anti-D polyclonal and monoclonal Abs and assessment of the possibility to manipulate the effector properties of the mAb. N-Glycosylation and particularly the content of nonfucosylated glycans are crucial for affinity of mAb to FcγRIIIA, which plays the key role in the clearance of sensitized cells. We studied and compared glycoprofiles and FcγRIIIA-mediated hemolytic ability of human polyclonal antibodies and anti-D mAbs produced by human B-cell lines, human-rodent heterohybridomas, and a human non-lymphoid cell line PER.C6. Replacement of producing cell line and use of glycosylation modulators can convert an inert mAb into an active one. Nevertheless, rodent cell lines, as well as human non-lymphoid cells, distort natural glycosylation of human IgG and could lead to the loss of immunosuppressive properties. All of the anti-D mAbs secreted by human B-cell lines have a glycoprofile close to human serum IgG. Hence, the constant ratio of IgG glycoforms in human serum is predetermined by glycosylation at the level of the individual antibody-producing cell. The anti-D fraction of polyclonal anti-D immunoglobulin compared to the total human IgG contains more nonfucosylated glycans. Thus, only human trans-formed B-cells are an appropriate source for efficient anti-D mAbs that can imitate the action of polyclonal anti-D IgG.

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Abbreviations

ADCC:

antibody-dependent cellular cytotoxicity

BCR:

B cell receptor

CHO:

Chinese hamster ovary cells

FcγR:

FcΓ receptor

LBL:

B-lymphoblastoid line cells

mAb:

monoclonal antibody

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Authors and Affiliations

  1. Hematology Research Center, Ministry of Health and Social Development, Noviy Zykovskiy Proezd 4A, 125167, Moscow, Russia

    N. I. Olovnikova & M. A. Ershler

  2. International Biotechnology Center “Generium”, Sadovaya-Triumfalnaya ul. 4-10, 127006, Moscow, Russia

    O. V. Grigorieva & A. V. Petrov

  3. Hematolog Ltd, Noviy Zykovskiy Proezd 5, 125167, Moscow, Russia

    G. Yu. Miterev

Authors
  1. N. I. Olovnikova
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  2. M. A. Ershler
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  3. O. V. Grigorieva
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  4. A. V. Petrov
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  5. G. Yu. Miterev
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Correspondence to N. I. Olovnikova.

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Original Russian Text © N. I. Olovnikova, M. A. Ershler, O. V. Grigorieva, A. V. Petrov, G. Yu. Miterev, 2012, published in Biokhimiya, 2012, Vol. 77, No. 8, pp. 1122–1132.

Originally published in Biochemistry (Moscow) On-Line Papers in Press, as Manuscript BM12-087, June 17, 2012.

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Olovnikova, N.I., Ershler, M.A., Grigorieva, O.V. et al. Impact on N-Glycosylation profile of monoclonal anti-D antibodies as a way to control their immunoregulatory and cytotoxic properties. Biochemistry Moscow 77, 925–933 (2012). https://doi.org/10.1134/S0006297912080147

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  • DOI: https://doi.org/10.1134/S0006297912080147

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