Modification of the Fc region of a primatized IgG antibody to human CD4 retains its ability to modulate CD4 receptors but does not deplete CD4(+) T cells in chimpanzees.
Keliximab, a Primatized IgG1 CD4 mAb, was reconfigured to an IgG4 antibody. The gamma4 constant region was further modified by substituting glutamic acid for serine at position 235 in the CH2 domain (IgG4-E), to remove residual binding to Fcgamma receptors, and substitution of serine with proline at position 228 in the hinge region (IgG4-PE) for greater stability. Pharmacokinetic analysis in rats gave a t(1/2) of approximately 4 days for IgG4-E and 9 days for IgG4-PE, consistent with a greater stability of the IgG4-PE molecule. The effects on T cell subsets were assessed in chimpanzees given escalating doses of IgG4-PE: 0.05 mg/kg on Day 16, 1.5 mg/kg dose on Day 43, and 15 mg/kg on Day 85. Receptor modulation was observed at the two highest doses, but no depletion of T cells at any dose. The in vitro and in vivo results demonstrate the potential of this IgG4-PE mAb for use in human trials.
Newman
R
R
IDEC Pharmaceuticals Corporation, 11011 Torreyana Road, San Diego, California, 92121, USA.
Hariharan
K
K
Reff
M
M
Anderson
D R
DR
Braslawsky
G
G
Santoro
D
D
Hanna
N
N
Bugelski
P J
PJ
Brigham-Burke
M
M
Crysler
C
C
Gagnon
R C
RC
Dal Monte
P
P
Doyle
M L
ML
Hensley
P C
PC
Reddy
M P
MP
Sweet
R W
RW
Truneh
A
A
D019943:Amino Acid Substitution; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000493:pharmacokinetics; D000915:Antibody Affinity; D001172:Arthritis, Rheumatoid / Q000628:therapy; D001665:Binding Sites; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D003001:Cloning, Molecular; D005803:Genes, Immunoglobulin; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000235:genetics; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007165:Immunosuppression Therapy / Q000379:methods; D008212:Lymphocyte Depletion; D008252:Macaca fascicularis; D008297:Male; D016297:Mutagenesis, Site-Directed; D002679:Pan troglodytes / Q000276:immunology*; D016133:Polymerase Chain Reaction; D011489:Protein Denaturation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017452:Receptors, IgG / Q000378:metabolism; D013329:Structure-Activity Relationship
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D007127:Immunoglobulin Constant Regions; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D017452:Receptors, IgG; C121870:clenoliximab; C121251:keliximab