Dm. Knight et al., CONSTRUCTION AND INITIAL CHARACTERIZATION OF A MOUSE-HUMAN CHIMERIC ANTI-TNF ANTIBODY, Molecular immunology, 30(16), 1993, pp. 1443-1453
Tumor necrosis factor-alpha (TNF) has been implicated in the pathogene
sis of a variety of human diseases including septic shock, cachexia, g
raft-versus-host disease and several autoimmune diseases. Monoclonal a
ntibodies directed against TNF provide an attractive mode of therapeut
ic intervention in these diseases. We have generated a murine monoclon
al antibody (A2) with high affinity and specificity for recombinant an
d natural human TNF. To increase its therapeutic usefulness, we used g
enetic engineering techniques to replace the murine constant regions w
ith human counterparts while retaining the murine antigen binding regi
ons. The resulting mouse-human chimeric antibody should have reduced i
mmunogenicity and improved pharmacokinetics in humans. Molecular analy
sis of light chain genomic clones derived from the murine hybridoma su
ggests that two different alleles of the same variable region gene hav
e rearranged independently and coexist in the same hybridoma cell. The
chimeric A2 antibody (cA2) exhibits better binding and neutralizing c
haracteristics than the murine A2 which was shown to contain a mixture
of two kappa light chains. The properties of cA2 suggest that it will
have advantages over existing murine anti-TNF antibodies for clinical
use.