Hybrid IgA2/IgG1 antibodies with tailor-made effector functions.
Immunoglobulin (Ig) A and IgG are the principal immune effector molecules at mucosal surfaces and in blood, respectively. Mucosal IgA is polymeric and bound to secretory component, whereas serum IgG is monomeric. We have now produced IgA2/IgG1 hybrid antibodies that combine the properties of IgA and IgG. Antibodies with Calpha3 at the end of the IgG H chain resemble IgA and form polymers with J chain that bind the polymeric Ig receptor. Like IgG, the hybrid proteins activated complement and bound FcgammaRI and protein A. Though the hybrid proteins contained both Cgamma2 and Cgamma3, they have a short in vivo half-life. Surprisingly, this decreased half-life correlated with a higher avidity than that of IgG for murine FcRn. Interestingly, antibodies with Calpha1 replacing Cgamma1 were resistant to extremes of pH, suggesting that Calpha1 increases antibody stability. These results provide insights into engineering antibodies with novel combinations of effector functions.
Chintalacharuvu
K R
KR
Department of Microbiology, Immunology, and Molecular Genetics, Molecular Biology Institute, University of California Los Angeles, 405 Hilgard Avenue, Los Angeles, California 90095, USA. kotec@lifesci.ucla.edu
Vuong
L U
LU
Loi
L A
LA
Larrick
J W
JW
Morrison
S L
SL
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003171:Complement Pathway, Classical; D006224:Cricetinae; D004285:Dogs; D006207:Half-Life; D015395:Histocompatibility Antigens Class I; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007070:Immunoglobulin A / Q000235:genetics* / Q000502:physiology*; D007127:Immunoglobulin Constant Regions / Q000502:physiology; D007074:Immunoglobulin G / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008958:Models, Molecular; D021381:Protein Transport; D011961:Receptors, Fc / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D019056:Receptors, Polymeric Immunoglobulin / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013205:Staphylococcal Protein A / Q000378:metabolism; D014162:Transfection
D015395:Histocompatibility Antigens Class I; D007070:Immunoglobulin A; D007127:Immunoglobulin Constant Regions; D007074:Immunoglobulin G; D011961:Receptors, Fc; D017452:Receptors, IgG; D019056:Receptors, Polymeric Immunoglobulin; D011993:Recombinant Fusion Proteins; D013205:Staphylococcal Protein A; C100688:Fc receptor, neonatal