Sponsored Links: Prescription Drug Addiction     STRATEGIC BRIEFINGS  Monoclonal Antibodies: From Magic Bullets to Successful Drugs By Lucy Sannes, Ph.D., Sannes & Associates Vicki Glaser, Contributing Editor to Pharma DD, contributed to this article. November 16, 2006 Monoclonal antibodies have been the focus of intensive research as potential therapeutic agents for more than a century. It was not until 1986, however, that the first monoclonal antibody-based therapy reached the market, Ortho Biotech’s Orthoclone OKT3 (muromonab-CD3), for the treatment of organ transplant rejection. Another eight years then passed until the second monoclonal antibody therapy—Centocor’s ReoPro (abciximab) to reduce complications of cardiac ischemia—obtained U.S. Food and Drug Administration (FDA) approval.   Monoclonal antibody–based therapies have proven to be major clinical and marketing successes, generating not only substantial revenues but also much-awaited recognition for the biotechnology industry, while at the same time capturing the interest of big pharma. Six of the antibodies on the market in the United States today have already reached blockbuster status, with sales exceeding $1 billion each. Antibodies currently on the market in the U.S. had combined global sales greater than $13 billion in 2005.   Amgen’s December 2005 announcement that it had agreed to acquire Abgenix for approximately $2.2 billion in cash plus assumption of debt further underscores the important and growing role monoclonal antibodies are playing in drug discovery. With this acquisition, Amgen acquired full rights to panitumumab (a human antibody in Phase III development) plus Abgenix’s technology for producing human antibodies.   To date, 17 therapeutic monoclonal antibodies have received FDA approval and are on the market in the U.S. (see Table 1 at end of article). In addition, several antibodies have been approved for use in diagnostic imaging applications. Another therapeutic antibody, Biogen Idec/Elan Pharmaceutical’s Tysabri (natalizumab) had received FDA approval in late 2004, but the companies withdrew the drug from the market in February 2005 because of safety concerns following reports of progressive multifocal leukoencephalopathy (PML). The companies resubmitted the drug to the FDA in September 2005, and Tysabri received Priority Review status. In February 2006, the FDA removed the hold on clinical trial dosing of Tysabri in relapsing multiple sclerosis in the U.S. and re-approved the drug in June 2006. Biogen Idec and Elan then reintroduced Tysabri in July.   More monoclonal antibody drugs should be expected on pharmacy shelves in the near future, as more than 40 antibody-based therapies are currently in late-stage (Phase II or III) clinical development (see Table 2 at end of article), and a substantial number are in earlier phases of clinical and preclinical testing.   Historical Ups and Downs   In 1975, Georges Kohler and Cesar Milstein discovered that hybridoma cells—hybrid cells formed by the fusion of an antibody-secreting murine lymphocyte cell with a myrine myleoma cell—grown in culture will produce monoclonal antibodies. Considerable hope (and hype) followed this discovery. Many believed that monoclonal antibodies would, in fact, be “magic bullets” for treating disease, a phrase coined by Novel Prize winner Paul Ehrlich. However, the next two decades yielded only two commercial monoclonal antibody–based therapeutics in the U.S. market.   The first monoclonal antibodies were murine antibodies. These mouse-derived antibodies satisfy a need in the in vitro diagnostics market and are used in clinical laboratories to detect antigens or antibodies in a patient's serum or other body fluids. However, when injected into humans as in vivo imaging agents or for therapeutic purposes, murine antibodies induce an immune reaction. The patient’s immune system recognizes them as foreign, often resulting in a human antimouse antibody, or HAMA, response. This can cause an allergic reaction in some patients, which, if the reaction is severe, can result in death.   Initial efforts to minimize the HAMA response primarily focused on genetic engineering of the antibodies. One early strategy involved the development of chimeric antibodies, which consist of the variable region of the mouse antibody combined with the constant region from a human antibody. To reduce the HAMA response even further, researchers created humanized antibodies that contained only the CDR region of the murine antibody; the rest of the antibody is of human origin. More recently, some companies have developed methods to generate fully human monoclonal antibodies. Other innovative approaches have included the use of antibody fragments.   The first two antibodies to reach the market in the U.S. were murine and chimeric antibodies, respectively, and additional murine and chimeric antibodies have since received FDA approval. However, as demonstrated by the antibodies listed in Tables 1 and 2, most of the therapeutic antibodies on the market and in development today are either humanized or human antibodies.   Therapeutic Opportunities   Monoclonal antibodies have the potential to treat a wide range of diseases. Cancer therapeutics represents one of the major areas in which monoclonal antibodies have been successful, including the treatment of both solid tumors and hematologic cancers. Eight of the antibodies on the market in the U.S. today are approved for the treatment of cancer. Among these are three of the six antibodies with more than $1 billion in individual sales in 2005. Genentech developed and currently markets all three of these blockbuster drugs in the U.S., while Roche holds marketing rights in the rest of the world. These three antibodies--Rituxan (rituximab, marketed as MabThera outside the U.S.) for treatment of non-Hodgkin’s lymphoma (NHL), Herceptin (trastuzumab) for treatment of breast cancer, and Avastin (bevasizumab) for treatment of metastatic colorectal cancer--represent three of Roche’s top five selling pharmaceutical products and had combined sales greater than $6 billion worldwide in 2005.   These Genentech/Roche antibodies, and most of the monoclonal antibodies now on the market or in late-stage development for the treatment of cancer, are naked, or unconjugated antibodies that function by targeting proteins associated the activity of cancerous cells. For example, Herceptin blocks the HER2 growth factor receptor that is over-expressed in some breast cancers, Rituxan targets the CD22 antigen found on certain lymphoma cells, and Avastin inhibits angiogenesis by targeting vascular endothelial growth factor (VEGF). This strategy of using unconjugated antibodies can clearly succeed in both the clinic and the market, and many other companies are pursing this approach. Unconjugated monoclonal antibodies in Phase III development for treatment of cancer include Amgen’s panitumumab (targeting EGFR), Immunomedics’ epratuzumab (targeting CD22), Bristol-Myers Squibb’s and Medarex’s MDX-010 (targeting the CTLA-4 receptor), Serono/Genmab’s zanolimumab (targeting the CD4 receptor), and United Therapeutics’ oregovomab (targeting CA125). These antibodies in late-stage clinical development demonstrate the wide range of proteins and cancers that monoclonal antibodies can target.   An alternative strategy for developing monoclonal antibodies as cancer therapeutics is to use the antibodies for targeted delivery of a cytotoxic drug or radioactive isotope to the tumor site. For radioimmunotherapy, the two most commonly used radioisotopes are iodine (I-131) and yttrium-90 (Y-90). Both are high-energy beta-emitting isotopes. The range of these beta particles extends beyond the cells targeted by the antibody, and thus they may also kill surrounding antigen-negative cells. This can potentially enhance the therapeutic efficacy of the antibody compared to an unlabeled antibody.   The first of two radioimmunotherapies to reach the U.S. market was Biogen Idec’s Zevalin (ibritumomab tiuxetan), approved in 2002 for treatment of NHL. Zevalin is a murine monoclonal antibody targeted against the CD20 antigen. The Zevalin kit contains materials for the preparation of both indium-111 Zevalin (for imaging) and Y-90 Zevalin (for therapy). Zevalin is administered together with the therapeutic antibody Rituxan. Sales of Zevalin have been limited. In 2004 (the last year for which data are available), U.S. sales of Zevalin were $18.7 million, compared to $19.6 million in 2003.   A second radioimmunotherapy, Bexxar, received FDA approval in 2003, also for treatment of NHL. Bexxar is an I-131 labeled antibody that has also had only limited sales. Bexxar was originally developed by Corixa, which, in December 2004, transferred all rights for Bexxar to its partner GlaxoSmithKline. In the press release announcing this agreement, Corixa indicated that it continued to believe in the promise of Bexxar, but that commercial acceptance of the product was too slow for Corixa to continue to fund the product.   While radioimmunotherapy represents a potentially promising strategy for treatment of cancer, it also has disadvantages. Acquisition and use of the radioisotope to label the antibody necessitates hospital-based care, making this approach more complicated than therapies involving unconjugated antibodies. A particular disadvantage of I-131, a radioisotope that is readily available and easy to use for antibody labeling, is its relatively long half-life of eight days. During that time, the isotope can dehalogenate from the antibody and cause thyroid damage.   Y-90 is a higher-energy isotope with a half-life of only 64 hours. It is preferred over I-131 for targets that are internalized by cells after the bind the antibody, as the Y-90 will be retained in the cell. However, Y-90 is incorporated into bone and can thus result in higher radiation doses to bone marrow than what occurs with I-131. Overall, radioimmunotherapy products have clearly demonstrated efficacy and the ability to gain FDA approval, but they have yet to realize commercial success. Additional radioimmunotherapeutic agents are in the early stages of development.   Monoclonal antibodies can also be used to deliver a cytotoxic drug to a tumor. In 2000, the first therapeutic antibody conjugated to a cytotoxic drug, Wyeth’s Mylotarg (gemtuzumab), was approved by the FDA. Mylotarg is a humanized antibody conjugated to the cytotoxic antitumor antibiotic calicheamicin. Regulatory approval covers the treatment of CD33-positive acute myeloid leukemia (AML). Currently, Mylotarg is the only antibody/cytotoxic drug conjugate available in the U.S., and no similar products are in late-stage clinical development.   Yet another permutation of this concept involves the use of monoclonal antibodies for targeted delivery of toxins to cancer cells. At this time, no immunotoxins have reached the market, although Cambridge Antibody Technology’s CAT-3888 is in Phase II development for hairy cell leukemia, and is in Phase I trials for chronic lymphocytic leukemia and pediatric acute lymphoblastic leukemia. CAT-3888 is a fusion protein that consists of a murine anti-CD22 disulphide-linked Fv antibody fragment (dsFv) and the modified Pseudomonas endotoxin PE38. Additional immunotoxins, including those from ImmunoGen, are in earlier stages of development.   A second major therapeutic area in which monoclonal antibodies have demonstrated both clinical and commercial success is immune-related disease. These include autoimmune diseases, inflammation, and immune suppression (for prevention of rejection following organ or tissue transplantation). Two blockbuster monoclonal antibodies with sales exceeding $1 billion each that target the immune system are Centocor’s Remicade (infliximab) and Abbott’s Humira (adalimumab). Both target tumor necrosis factor alpha (TNF-alpha), although Remicade is a chimeric antibody and Humira is a human antibody. Remicade is currently indicated for treatment of rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, psoriatic arthritis, and ulcerative colitis. Humira received FDA approval for treatment of rheumatoid arthritis and psoriatic arthritis. Both of these antibodies compete against Amgen’s Embrel (etalercept), which is not a true monoclonal antibody but rather is a fusion protein that consists of the extracellular ligand-binding portion of TNF receptor (TNFR) linked to the Fc portion of human IgG1.   In addition to cancer and immune-related diseases, monoclonal antibodies have potential therapeutic efficacy in a host of other diseases. For example, MedImmune’s Synagis (palivizumab) is used for passive immunotherapy to prevent infection by respiratory syncytial virus (RSV). Sales of Synagis exceeded $1 billion for the first time in 2005. Centocor’s ReoPro (abciximab) is used to reduce complications from cardiac ischemia.   The market for therapeutic monoclonal antibodies is large and well established and continues to grow dramatically each year. Continuing rapid growth in sales of currently available monoclonal antibodies (especially the “blockbuster” drugs), combined with the introduction of new therapeutic antibodies, is fueling market expansion. More than 40 new monoclonal antibodies are in Phase II or later development (Table 2), and this figure does not include antibodies already on the market that are being developed for additional indications. Many more antibody-based products are in earlier clinical or preclinical development, setting the stage for a continued and perhaps expanding influx of monoclonal antibody therapeutics.   Table 1:  FDA-Approved Monoclonal Antibody–Based Therapeutics Company Name(s) Trade (Generic) Names Global 2005 Sales (millions) Target Antigen Type of Antibody FDA-Approved Indication(s) Year of FDA Approval Ortho Biotech (Johnson & Johnson) Orthoclone OKT3 (muromonab-CD3) -- CD3 Murine For treatment of acute allograft rejection in renal transplant patients, and for treatment of steroid-resistant acute allograft rejection in cardiac and hepatic transplant patients. 1986 Centocor (Johnson & Johnson) (Marketed by Eli Lilly except in Japan ) ReoPro (abciximab) $363 (2004) GP IIb/IIIa receptor Fab fragment of a chimeric antibody For use as an adjunct to percutaneous coronary intervention for prevention of cardiac ischemia complications in patients undergoing percutaneous coronary intervention, and also in patients with unstable angina who do not respond to conventional therapy when percutaneous coronary intervention is planned within 24 hours. 1994 Genentech, Roche, Biogen Idec Rituxan/ MabThera (rituximab) $3,300 (4,154 million CHF) CD20 Chimeric For treatment of relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin’s lymphoma (NHL). 2/06: Approved for use in first-line treatment of patients with diffuse large B-cell, CD20-positive NHL, in combination with CHOP (cyclophosphamide, doxorubicin, vincristin and prednisone) or other anthracycline-based chemotherapy regimen. 1997 Genentech and Novartis Ophthalmics and Roche (through Genentech) Lucentis (ranibizumab) --   VEGF   Antibody fragment to vascular endothelial growth factor (VEGF); inhibits angiogenesis. 2006 Hoffmann-La Roche Zenapax (daclizumab) -- IL2 receptor Humanized For prophylaxis of acute organ rejection in renal transplant patients. 1997 Novartis Simulect (basiliximab) -- IL2 receptor Chimeric For prophylaxis of acute organ rejection in renal transplant patients when used as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids. 1998 MedImmune Synagis (palivizumab) $1,063 RSV Humanized For prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients at high risk of RSV disease. 1998 Centocor (Johnson & Johnson) (Distributed by Schering-Plough outside US, except in Japan and parts of Far East ) Remicade (infliximab) $2,535 reported by J&J, plus $942 reported by Schering-Plough TNF-alpha Chimeric For treatment of rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, psoriatic arthritis, and ulcerative colitis. 1998 Genentech and Roche Herceptin (trastuzumab) $1,700 (2,146 million CHF) HER2 protein Humanized For treatment of metastatic breast cancer in women whose tumors overexpress the HER2 protein (as a first-line therapy in combination with paclitaxel, and as a single agent for second- and third-line therapy. 1998 Wyeth Mylotarg (gemtuzumab ozogamicin) -- CD33 Humanized (conjugated to the cytotoxic antitumor antibiotic calicheamicin) For treatment of patients with CD33 positive acute myeloid leukemia (AML) in first relapse who are 60 years of age or older and who are not candidates for other cytotoxic chemotherapy. 2000 Genzyme (Marketed by Schering AG outside US, Berlex Laboratories in US) Campath (alemtuzumab) -- CD52 Humanized For treatment of B-cell chronic lymphocytic leuckemia (B-CLL) in patients who have been treated with alkylating agents and who have failed fludarabine therapy. 2001 Biogen Idec (Marketed by Schering AG outside the US) Zevalin (ibritumomab tiuxetan) $18.7 (US 2004 sales) CD20 Murine (In-111 and then Y-90 labeled) For treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, including patients with rituximab refractory follicular NHL. 2002 Abbott Laboratories Humira (adalimumab) $1,400 TNF-alpha Human For treatment of adults with rheumatoid arthritis and psoriatic arthritis. 2002 Genentech, Novartis, Tanox,  Roche (through Genentech) Xolair (omalizumab) $321 (US sales) IgE Humanized For treatment of adults and adolescents with moderate to severe persistent asthma. 2003 GlaxoSmithKline (Originally developed by Corixa) Bexxar (tositumomab and I-131 tositumomab) Corixa reported sales of $2.5 million in 3Q04, $2.2 million in 2Q04, and $1.3 million in 1Q04. CD20 Murine (I-131 labeled) For treatment of patients with CD20-expressing relapsed or refractory, low-grade, follicular, or transformed NHL (including patients with rituximab-refractory NHL). 2003 Genentech and Roche Raptiva (efalizumab) $79 (US sales) CD11a Humanized For treatment of adults with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. 2003 ImClone Systems, Bristol-Myers Squibb, Merck KgaA Erbitux (cetuximab) $413 (US sales) EGFR Chimeric For use in combination with irinotecan to treat irinotecan-resistant EGFR-expressing metastatic colorectal cancer. Also approved for use as a single agent to treat EGFR-expressing metastatic colorectal cancer in patients who are intolerant of irinotecan-based chemotherapy. 2004 Genentech and Roche Avastin (bevacizumab) $1,700 (2,146 million CHF) VEGF Humanized For use in combination with 5-fluorouracil-based chemotherapy as a first-line treatment of patients with metastatic colon cancer or rectal cancer. 2004