derived by immunization of non-transgenic mice. Panitumumab (Vectibix™)

against EGFR was the first human MAb obtained using transgenic mice that got

FDA approval in 2006 for clinical use in colorectal, non-small cell lung cancer, and

renal cell carcinoma (Chua and Cunningham 2006). Table 22.3 lists some of the

human therapeutic MAbs produced using transgenic mice.

22.4.2 Phage-Display-Derived Therapeutic Human Antibodies

Transgenic humanized mice led to successful development of several therapeutic

human MAbs; however, to generate antibodies against toxin and unstable antigens

required alternate technology. In vitro selection technologies such as antibody phage

display do not depend on the in vivo immune response and thus can be used to make

antibodies to almost every type of antigen. This approach is based on the ground-

breaking work of George P. Smith who demonstrated the feasibility of expression of

peptides on filamentous E. coli phage M13 (Smith 1985). Antibody phage-display

technology has been further facilitated by the discovery of small recombinant

antibody formats such as single-chain variable fragment (scFv) and their ability for

periplasmic expression and secretion in E. coli (Bird et al. 1988; Skerra and

Pluckthun 1988). Subsequently, phage-display antibody libraries have been devel-

oped expressing either scFv (Vaughan et al. 1996) or fragment antigen-binding (Fab)

Table 22.3 Partial list of therapeutic human MAbs produced by using transgenic mice

Product

Trade

name

Indication

Target

Company (FDA

approval)

Panitumumab

Vectibix™

Metastatic colorectal cancer

EGFR

Amgen (2006)

Canakinumab

Ilaris™

Cryopyrin-associated periodic

syndromes including familial

cold, autoinflammatory

syndrome, and Muckle-Wells

syndrome

IL-1β

Novartis (2009)

Golimumab

Simponi™

Rheumatoid and psoriatic

arthritis, active ankylosing

spondylitis

TNF-α

Centocor, Ortho

Biotech

(Johnson &

Johnson) (2009)

Ustekinumab

Stelara™

Plaque psoriasis

IL-12/

IL-23

Centocor, Ortho

Biotech

(Johnson &

Johnson) (2009)

Ofatumumab

Arzerra™

Chronic lymphocytic leukemia

CD20

Genmab and

GSK (2009)

Denosumab

Prolia™

Treatment of postmenopausal

osteoporosis

RANKL

Amgen (2010)

Ipilimumab

Yervoy™

Melanoma

CTLA-4/

CD152

BMS (2011)

408

S. K. Gupta and P. Chaudhary