Recombinant mouse monoclonal antibodies with single amino acid substitutions affecting Clq and high affinity Fc receptor binding have identical serum half-lives in the BALB/c mouse.
The serum half-lives of three recombinant mouse monoclonal antibodies, differing radically in their ability to bind to Clq or FcRI but only minimally in structure, were determined in the BALB/c mouse following intravenous administration. The wild-type antibody, a chimaeric antibody comprising variable domains binding 3-iodo-4-hydroxy-5-nitrophenylacetate and constant domains of the mouse IgG2b isotype, was eliminated from the bloodstream with biphasic kinetics: alpha-phase, 0.5 days; beta-phase, 7.0 days. The alpha- and beta-phase half-lives of mutant recombinant antibodies with single amino acid substitutions, either Glu 235-Leu allowing binding to the mouse FcRI, or Lys 322-Ala reducing Clq binding 30-fold, were indistinguishable from those of the wild-type antibody demonstrating that the biological half-life of intact mouse IgG is independent of the ability to bind Clq or FcRI. The major implication of the present study is that IgG molecules which have been genetically engineered to eliminate interaction with other components of the immune system should retain the long half-life typical of natural antibodies.
Wawrzynczak
E J
EJ
Drug Targeting and Immunophysiology Laboratories, Institute of Cancer Research, Sutton, Surrey, U.K.
Denham
S
S
Parnell
G D
GD
Cumber
A J
AJ
Jones
P T
PT
Winter
G
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003166:Complement Activating Enzymes / Q000378:metabolism; D005260:Female; D006207:Half-Life; D018960:Hyaluronan Receptors; D007074:Immunoglobulin G / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D024101:Mitochondrial Proteins; D009154:Mutation; D015202:Protein Engineering; D011951:Receptors, Complement / Q000378:metabolism*; D011961:Receptors, Fc / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics*
D000911:Antibodies, Monoclonal; C490193:C1qbp protein, mouse; D018960:Hyaluronan Receptors; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D024101:Mitochondrial Proteins; D011951:Receptors, Complement; D011961:Receptors, Fc; D011994:Recombinant Proteins; C032402:complement 1q receptor; D003166:Complement Activating Enzymes