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Humanization of the anti-CD18 antibody 6.7: an unexpected effect of a framework residue in binding to antigen.

Abstract：

:Humanization of monoclonal antibodies by complementary determinant region (CDR)-grafting has become a standard procedure to improve the clinical usage of animal antibodies. However, antibody humanization may result in loss of activity that has been attributed to structural constraints in the framework structure. In this paper, we report the complete humanization of the 6.7 anti-human CD18 monoclonal antibody in a scFv form. We used a germline-based approach to design a humanized VL gene fragment and expressed it together with a previously described humanized VH. The designed humanized VL has only 14 mutations compared to the closest human germline sequence. The resulting humanized scFv maintained the binding capacity and specificity to human CD18 expressed on the cell surface of peripheral blood mononuclear cells (PBMC), and showed the same pattern of staining T-lymphocytes sub-populations, in comparison to the original monoclonal antibody. We observed an unexpected effect of a conserved mouse-human framework position (L37) that hinders the binding of the humanized scFv to antigen. This paper reveals a new framework residue that interferes with paratope and antigen binding and also reinforces the germline approach as a successful strategy to humanize antibodies.

journal_name

Mol Immunol

journal_title

Molecular immunology

authors

Caldas C,Coelho V,Kalil J,Moro AM,Maranhão AQ,Brígido MM

doi

10.1016/s0161-5890(03)00022-1

subject

Has Abstract

pub_date

2003-05-01 00:00:00

pages

941-52

issue

15

eissn

0161-5890

issn

1872-9142

pii

S0161589003000221

journal_volume

39

pub_type

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