       Document 0409
 DOCN  M9610409
 TI    Influence of heavy chain constant regions on antigen binding and HIV-1
       neutralization by a human monoclonal antibody.
 DT    9601
 AU    Cavacini LA; Emes CL; Power J; Desharnais FD; Duval M; Montefiori D;
       Posner MR; Department of Medicine, New England Deaconess Hospital,
       Boston,; MA 02215, USA.
 SO    J Immunol. 1995 Oct 1;155(7):3638-44. Unique Identifier : AIDSLINE
       MED/96016013
 AB    F105, a neutralizing IgG1 kappa human mAb, is reactive with a
       discontinuous epitope within the gp120 CD4 binding site. Because isotype
       usage may affect Ab function, we examined the effect of isotype on Ag/Ab
       interactions and HIV-1 neutralization. An IgG3 kappa Ab was prepared by
       linking the variable regions of F105 to cloned human kappa and gamma 3
       constant regions. Immunoreactivity of F105 IgG1 and IgG3 with IIIB-,
       MN-, and RF-infected cells was equivalent. Inhibition of binding and
       fusion of IIIB to uninfected cells and neutralization of IIIB virus was
       comparable for F105 IgG1 and IgG3, with 14 to 23 micrograms/ml required
       for 90% neutralization. In contrast, F105 IgG3 was marginally more
       effective at inhibition of MN binding/fusion and significantly more
       effective at neutralization of MN virus (62 micrograms/ml for IgG3 and >
       100 micrograms/ml for IgG1 to achieve 90% neutralization). Despite high
       affinity binding to RF-infected cells, F105 IgG1 minimally neutralizes
       free RF virus. F105 IgG3 is dramatically more effective against the RF
       isolate, with 2 to 20 micrograms/ml of Ab required for 50%
       neutralization. Both isotypes were relatively ineffective at inhibition
       of RF binding/fusion. Thus, whereas affinity with native Ags on the
       surface of HIV-1-infected cells was unaffected by heavy chain constant
       regions, Ab isotype can strongly influence virion neutralization.
       Structural changes in gp120, as a result of increased flexibility
       conferred by the elongated IgG3 hinge region, are suggested as a
       possible mechanism to increase neutralization of selected HIV-1
       isolates. These results may have significant implications in the design
       of immunotherapeutic and vaccine agents.
 DE    Antibodies, Monoclonal/IMMUNOLOGY  Epitopes  Human  HIV/*IMMUNOLOGY  HIV
       Antibodies/*IMMUNOLOGY  HIV Envelope Protein gp120/*IMMUNOLOGY
       Immunoglobulins, Heavy-Chain/*IMMUNOLOGY  Support, Non-U.S. Gov't
       Support, U.S. Gov't, P.H.S.  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

