22.2

Mouse-Human Chimeric MAbs

Chimeric antibodies are made by genetic engineering that involves grafting of the

variable domains of light and heavy chains of the murine MAb to human constant

domains of light and heavy chains (Morrison et al. 1984; Fig. 22.1). It took a decade

for the first chimeric MAb, abciximab for homeostasis, to be approved by the FDA in

1994 (Faulds and Sorkin 1994). Abciximab is made from the Fab fragments of an

immunoglobulin that targets the glycoprotein IIb/IIIa receptor on the platelet mem-

brane (Table 22.1). It is a platelet aggregation inhibitor and mainly used during and

after coronary artery procedures like angioplasty to prevent platelets from sticking

together and causing thrombus formation within the coronary artery. Rituximab,

another chimeric MAb against CD20, was developed to treat non-Hodgkin’s lym-

phoma, chronic lymphocytic leukemia, transplant rejection, and rheumatoid arthritis

(Table 22.1). It destroys both normal and malignant B cells that have CD20 on their

surface. Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor, given

by intravenous infusion for the treatment of metastatic colorectal and head and neck

cancer. Table 22.1 also summarizes additional chimeric MAbs that have been

approved by the FDA for clinical applications.

22.3

Humanized MAbs

To further reduce the murine content of mouse-human chimeric antibodies, only

complementarity-determining regions (CDRs) have been grafted onto the human

framework regions (FR) giving rise to “humanized” antibodies (Kettleborough et al.

Fig. 22.1 Schematic diagram to show the progression of therapeutic antibodies: Initially murine

MAbs have been proposed for therapeutic application in humans. Repeated use of murine

antibodies in humans leads to the generation of the human anti-mouse antibodies. To reduce the

immunogenicity of mouse antibodies, subsequently chimeric, humanized, and finally full human

antibodies have been developed for their clinical use in humans

22

Therapeutic Human Monoclonal Antibodies

403