Hmfg

Lewis Y antigen Colorectal antigen Prostate antigen

TNFa I FN 7

RSV F-protein HSV-1 gB HSV-1 gD HIV-1 IIIB gp120 HIV-1 MN gp120

Celltech/RW Johnson PRI Cambridge Pathology Genentech

Celltech/RW Johnson PRI Cambridge Pathology Immunomedics ProteinDesignLabs/Roche Glaxo-Wellcome Celltech/American Cyanamid Protein Design Labs Protein Design/Yamanouchi Scotgen/Biogen Glaxo-Wellcome Scotgen/Medarex Icos Corp

MRC/E Merck

Genentech

Celltech

Behringwerke

Scotgen/Dow

Scotgen/lmmunomedics

Scotgen/Dow

Celltech/American Cyanamid Protein Design Labs/Sandoz Celltech/American Cyanamid Scotgen/Cytogen

Celltech/Bayer Protein Design Labs

Scotgen/SmithKline Beecham Protein Design Labs Protein Design Labs MRC Collaborative Centre Scotgen/Nissin

EGFR. epidermal growth factor receptor; HIV, human immunodeficiency virus; HSV, herpes simplex virus; I FN, interferon; RSV. respiratory syncytial virus.

Adapted from Adair and Bright (1995)

indirect methods have been developed to restore antigen binding affinity to a humanized antibody.

A major aspect is the selection of human VH and VK genes as acceptor molecules. A wide range of adult human immunoglobulin genes have been cloned which represent all seven families of VH and VK in the human genome and the entire germ line repertoire of human VH and VK has been sequenced. Two general strategies for humanization have been developed to exploit these resources.

1. CDR grafting using human V,, and VK frameworks with the highest linear amino acid sequence homology to the donor rodent frameworks (homology matching). With this approach, the likelihood of the human framework having the same amino acid residue as the rodent in a 'crucial' position is maximized. Different human VH and Vk combinations are used with each antibody and may include combinations not used in nature.

Table 2 Representative examples of humanized antibodies in cynomologous monkeys and humans

Antibody

Doses (mg kg'1)

Monkeys

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