Functional properties of antibody insulin-like growth factor fusion proteins.
Genetic engineering and expression techniques have been used to produce antibody growth factor fusion proteins. Insulin-like growth factors (IGFs) 1 and 2 have been fused to mouse-human chimeric IgG3 at the end of CH1, immediately after the hinge, and at the end of CH3. Fusion heavy chains of the expected molecular weight were expressed, assembled with a co-expressed light chain, and secreted. The resulting molecules continued to bind antigen; they also bound the growth factor receptors, albeit with decreased affinity. The molecule with IGF1 attached after CH3 (CH3-IGF1) had reduced ability to carry out complement-mediated cytolysis. In contrast the molecule with IGF2 attached after CH3 (CH3-IGF2) showed an approximately 50-fold increase in its ability to effect complement-mediated cytolysis and so should be an effective cytolytic agent. Both CH3-IGF1 and CH3-IGF2 bound Fc gamma RI with affinity similar to that of IgG3. The growth factor fusion proteins showed small but significant uptake into the brain parenchyma.
Shin
S U
SU
Alkermes, Inc., Cambridge, Massachusetts 02139.
Friden
P
P
Moran
M
M
Morrison
S L
SL
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D015922:Complement C1q / Q000378:metabolism; D005803:Genes, Immunoglobulin; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000096:biosynthesis / Q000378:metabolism; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis / Q000378:metabolism*; D007700:Kinetics; D008214:Lymphocytes / Q000378:metabolism; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism*
D007127:Immunoglobulin Constant Regions; D007074:Immunoglobulin G; D017527:Receptor, IGF Type 2; D011993:Recombinant Fusion Proteins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D015922:Complement C1q; D017526:Receptor, IGF Type 1