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AIDS. 2014 Nov 13;28(17):2523-30. doi: 10.1097/QAD.0000000000000444.

Identification of antibody glycosylation structures that predict monoclonal antibody Fc-effector function.

Author information

1
aRagon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA bDepartment of Biochemistry, University of Oxford, Oxford, UK cNew York University School of Medicine, New York City, New York dDepartment of Computer Science eThayer School of Engineering, Dartmouth College, Hanover, New Hampshire fNew York Veterans Affairs Harbor Healthcare System, New York City, New York, USA.

Abstract

OBJECTIVE:

To determine monoclonal antibody (mAb) features that predict fragment crystalizable (Fc)-mediated effector functions against HIV.

DESIGN:

Monoclonal antibodies, derived from Chinese hamster ovary cells or Epstein-Barr virus-immortalized mouse heteromyelomas, with specificity to key regions of the HIV envelope including gp120-V2, gp120-V3 loop, gp120-CD4(+) binding site, and gp41-specific antibodies, were functionally profiled to determine the relative contribution of the variable and constant domain features of the antibodies in driving robust Fc-effector functions.

METHODS:

Each mAb was assayed for antibody-binding affinity to gp140(SR162), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and for the ability to bind to FcγRIIa, FcγRIIb and FcγRIIIa receptors. Antibody glycan profiles were determined by HPLC.

RESULTS:

Neither the specificity nor the affinity of the mAbs determined the potency of Fc-effector function. FcγRIIIa binding strongly predicted ADCC and decreased galactose content inversely correlated with ADCP, whereas N-glycolylneuraminic acid-containing structures exhibited enhanced ADCP. Additionally, the bi-antenary glycan arm onto which galactose was added predicted enhanced binding to FcγRIIIa and ADCC activity, independent of the specificity of the mAb.

CONCLUSIONS:

Our studies point to the specific Fc-glycan structures that can selectively promote Fc-effector functions independently of the antibody specificity. Furthermore, we demonstrated antibody glycan structures associated with enhanced ADCP activity, an emerging Fc-effector function that may aid in the control and clearance of HIV infection.

PMID:
25160934
PMCID:
PMC4429604
DOI:
10.1097/QAD.0000000000000444
[Indexed for MEDLINE]
Free PMC Article

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