NEWS FEATURE company’s fully-human transgenic mouse and Mice with a human touch is in phase 3 clinical testing for bone resorption in postmenopausal women. Years of tinkering with the mouse immune system genes has Rough waters for a superagonist finally produced a winner, with the approval of the first fully human But not everything was smooth sailing for monoclonal antibody made in a mouse. A real breakthrough or an new candidates and the companies that made them. The most widely publicized casualty is incremental improvement? Christopher Thomas Scott investigates. Germany’s TeGenero. The company’s lead drug, TGN1412, was a chimeric drug made by fusing mouse and human cells. Six male volunteers In September, 2006, the monoclonal antibody suffered severe immune responses during the Vectibix (panitumumab), offered by Thousand company’s disastrous phase 1 trial, conducted in Oaks, California–based Amgen, gained US Food the spring of 2006 at London’s Northwick Park and Drug Administration (FDA) approval for Hospital2. epidermal growth factor receptor (EGFR)- The clinical trial spelled the end for TeGenero, expressing colorectal cancers, the first totally which went bankrupt that summer. Peter human antibody made in a transgenic mouse. Parham, a Stanford University immunologist The 20-year quest to humanize mouse antibod- who studies the biology and evolution of major ies to avoid host immune responses had finally histocompatibility complex class I molecules, reached fruition. recalled hearing the TeGenero news. “I thought But the path to success has had its share of monoclonals would die on the vine,” he recalls. drama, with a patent dispute between two com- Figure 1 Engineering tour de force—the “But after looking at recent results, it looks like http://www.nature.com/naturebiotechnology panies with competing humanizing mouse plat- Xenomouse. Inactivating the mouse’s own they will do all right after all.” Parham singles forms that left one nearly penniless. And while antibody genes while supplying human out Rituxan (rituximab) offered by Genentech all this was going on, a rash of less than totally counterparts has led to the first fully human mAb and Biogen Idec, of Cambridge, Massachusetts, human antibodies has entered the clinic, largely drug made in a transgenic mouse. Source: Aya a chimeric mAb that targets CD20+ B cells, without incident, though one disastrous clinical Jakobovitz. which has been given to 600,000 lymphoma and trial could have brought the sector to its knees. arthritis patients as a case in point, noting the And if that weren’t enough, Vectibix’s target regions on a human scaffold— have gained fast drug’s safety record and gradual expansion for is in the cross hairs of several other marketed acceptance as an effective class of therapeutics. use in cancer and autoimmune disease. antibodies as well as some drugs in clinical tri- Current generation drugs include humanized Despite the trouble with TGN1412, the als. Whether Vectibix will be met with the same compounds such as the S. San Francisco–based market remains piping hot for approved prod- excitement in the clinic as it has in the board- Genentech’s breast cancer drug Herceptin ucts. Rituxan, Synagis and Centocor’s ReoPro Nature Publishing Group Group Nature Publishing 7 room remains to be seen. But at least for the (trastuzumab). Chimeric technologies include (abiciximab) each have annual revenues south moment, the spotlight is on the rodent that the anti-tumor necrosis factor (TNF) antibody of $3 billion. Since 1997, 18 mAb-based drugs 200 © made it, the Xenomouse (Fig. 1). Remicade (infliximab) produced by Centocor, have found the market, and 150 more are under a subsidiary of Johnson and Johnson, located development3. The mAb development timelines, Monoclonal saga in Horsham, Pennsylvania and prescribed from fully mouse in 1975 to fully human in 2006, Two years after Niels Jerne, César Milstein and for Crohn’s desease and arthritis. The first have averaged about 12 years—altogether strong George Köhler received the 1984 Nobel prize fully human mAb, the phage display–gener- performances for a field so young. in physiology or medicine for developing the ated Humira (adalimumab) from Abbott of technology to produce monoclonal antibodies Abbott Park, Illinois, and Cambridge Antibody The race for the fully humanized mouse (mAbs), the FDA approved the first mouse mAb Technology, a subsidiary of AstraZeneca of ‘Humanized’ mice with functional immuno- product, Orthoclone OKT3 (muromab), made London, is an anti-TNF-α drug targeting globulin loci of their own express both mouse by Johnson & Johnson of New Brunswick, New Crohn’s disease, rheumatoid arthritis and anky- and human antibodies and yield some, but not Jersey. The drug targeted human T-cell CD3 losing spondylitis. all, of the diversity present in a natural system. antigen and was prescribed to prevent rejection Though cancer and autoimmune diseases are The primary limitation of most approved mAb of transplanted kidneys1. Its shortcomings pre- prime foci for many mAb drugs, new targets have drugs is the immune response in patients who saged the major problem with this class of drug: emerged, such as AIDS and severe acute respi- take them—usually against the remaining after the first treatment, the patient makes anti- ratory syndrome (SARS). Human respiratory mouse components of the antibody. Making bodies against the constant (C) regions of the syncytial virus (RSV) infections, which cause transgenic mice that produced fully human mouse antibody, decreasing its effectiveness and significant mortality in infants, are successfully antibodies, while making none of their own, increasing the likelihood of complications. treated with a humanized anti-RSV antibody, became the next technical hurdle. To get around the immunogenetic properties Synagis (palivizumab) made by Medimmune Like many things in biotech, it was a race of mAbs, researchers began a quest using genetic of Gaithersburg, Maryland. Synagis is chime- to get there. In 1994, two San Francisco Bay engineering to make hybrid products combin- ric: six variable regions from the mouse mAb Area companies, GenPharm and Cell Genesys, ing mouse variable (V) regions with human C are inserted into a human IgG framework. A reported they had engineered mice to make regions. As a result, chimeric and humanized third targets RANKL, a TNF-family member fully human antibodies, now commonly called mAbs—those with murine variable regions stimulating the activation of osteoclasts. The ‘HumAb’ mice. The GenPharm method, devel- or murine complementarity-determining drug, Amgen’s denosomab, was made using the oped by its chief scientist, Nils Lonberg, now NATURE BIOTECHNOLOGY VOLUME 25 NUMBER 10 OCTOBER 2007 1075 NEWS FEATURE senior vice president and scientific director Cell Genesys spun out Abgenix in 1996, senior vice president and chief scientific officer at Medarex in Princeton, New Jersey, used with the mouse as its mascot. The company at privately owned Agensys in Santa Monica, homologous recombination to disrupt the searched for a partner to develop its anticancer California, “was to deliver the entire immuno- mouse immunoglobulin genes and pronuclear drug, now known as Vectibix, which targets the globulin locus into the mouse germ line. We injection to deliver components of light and EGFR. It found one in Seattle-based Immunex. successfully transferred megabyte-sized pieces heavy human transgenes, including constant Amgen acquired Immunex in 2002, and with it of human immunoglobulin into a murine and variable (V), diversity (D) and joining (J) the Abgenix codevelopment deal. The biotech humoral immune system.” Amgen now offers regions. The Cell Genesys group also disabled giant liked what it saw, and completed the circle six strains of mice making human IgG1, 2 and the mouse machinery, but used protoplasts to in 2005, buying Abgenix for $2.2 billion4. It 4 heavy chains in combination with the human deliver large fragments of the relevant chro- managed the last stages of clinical trials and kappa and lambda light chain sequences. mosomes with a yeast artificial chromosome Vectibix was approved for colorectal cancer in In a parallel trajectory, GenPharm pushed (YAC) system. In both cases, the constructs 2006, the first approved fully human mAb prod- ahead, but not without causing a ruckus. Cell went through VDJ joining, a natural process uct made from any human Ig mouse technology, Genesys sued them in 1994 for theft of trade producing antibody diversity. In addition, called the XenoMouse (see p. 1127, this issue). secrets. GenPharm returned the favor with an B cells with a low affinity for the antigen Aya Jakobovits, originally at Cell Genesys and infringement countersuit, and the fight was on. embark on T-cell affinity maturation, which later at Abgenix, shepherded the XenoMouse For venture-backed GenPharm, it became a war relies on somatic mutations to make antibod- through its entire development. The strategy for of attrition. Cell Genesys, a public company ies that bind tightly to the target. the new technology, says Jakobovits, who is now backed by government-owned Japan Tobacco, Box 1 A crowded space Vectibix is far from the only drug targeting EGFR. One Genmab’s pivotal phase 3 results for head and neck cancer are in, http://www.nature.com/naturebiotechnology chimeric antibody, Erbitux (cetuximab) is approved and several a clinical comparison between the two molecules could uncover humanized mAbs are under development. Among the approved information about the efficacy and safety of the IgG class of drugs. EGFR-targeting drugs there are no head-to-head comparisons. On other fronts, a humanized mAb targeting EGFR, TheraCIM Like Vectibix, Erbitux, marketed by New York’s ImClone and (nimotuzumAb), has been approved in Argentina, China, Princeton, New Jersey’s Bristol-Myers Squibb, targets the Columbia, India and Cuba for inoperable head and neck cancer. extracellular domain EGFR for colorectal cancer. No clinical In August, the Ontario, Canada drugmaker YM Biosciences trial has fully tested the differences between a chimeric and announced it was targeting colorectal cancer, using the drug fully human product.