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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

Source: Sannes & Associates, Inc.

Table 2: Companies Developing Monoclonal Antibodies and/or MAb-Based Therapeutics

(This table includes therapeutic antibodies in Phase II or later stage development, plus antibodies on the market for which additional indications are in development. Antibodies currently on the market that are not undergoing additional clinical development are not included.)

(Note: Does not include in vitro or in vivo diagnostic products, unless the in vivo diagnostic/imaging application is part of a therapeutic product.)

Company Name(s)	MAb		Clinical Phase		Comments
Amgen	panitumumab (rHuMAb-EGFr))		Phase III		•Human monoclonal antibody that targets the epidermal growth factor receptor (EGFR). •In Phase III for colorectal cancer. Being evaluated for treatment of a number of different cancers (solid tumors). Positive Phase III results were announced 11/05. •Was granted Fast Track designation from the FDA. •Development partner: Abgenix
Aphton (Acquired Igeneon)	IGN101		Phase II/III		•Murine monoclonal antibody 17A-1 absorbed on aluminum hydroxide. •A cancer vaccine that induces an immune response against EpCAM positive tumor cells. •In Phase II/III trial for treatment of non-small cell lung cancer.
Biogen Idec and PDL BioPharma	volociximab		Phase II		•Anti-alpha5 beta1 integrin (a cell adhesion molecule) •Inhibits angiogenesis •In Phase II trials in patients with advanced solid tumors that include renal cancer, pancreatic cancer, non-small cell carcinoma, and melanoma. •Originally developed by Protein Design Labs (now PDL BioPharma). In 8/05, Biogen Idec and Protein Design Labs announced a collaboration that included volociximab.
Biogen Idec	Anti-CD80 Mab (galiximab)		Phase II		•For non-Hodgkin’s B-cell lymphoma
Biogen Idec	Anti-CD23 Mab (lumiliximab)		Phase II		•For chronic lymphocytic leukemia
Cambridge Antibody Technology	CAT-3888		Phase II		•Immunotoxin fusion protein incorporating a murine anti-CD22 disulphide-linked Fv antibody fragment (dsFv) and the modified Pseudomonas endotoxin PE38. •In Phase II for hairy cell leukemia and in Phase I trials for chronic lymphocytic leukemia and for pediatric acute lymphoblastic leukemia.
Genentech and Roche	Avastin (bevacizumab)		On the market Submitted for approval for second-line therapy for colorectal cancer In development for additional indications		•Humanized monoclonal antibody fragment targeted to VEGF, thus preventing interaction of VEGF with VEGFR-1 (Flt-1) and VEGFR-2 (KDR). •FDA approved for use in combination with 5-fluorouracil-based chemotherapy as a first-line treatment of patients with metastatic colon cancer or rectal cancer. •Submitted to FDA for approval as a second-line therapy for colorectal cancer. •Also being developed for treatment of other cancers including metastatic breast cancer, non-small cell lung cancer, colorectal cancer (as second line therapy), ovarian cancer, pancreatic cancer, prostate cancer, and renal cell carcinoma.
Genentech and Roche and Biogen Idec	Rituxan (rituximab)		On the market (NHL) Phase III for chronic lymphocytic leukemia (CLL)		•Chimeric monoclonal antibody targeted against the CD20 antigen on the surface of B lymphocytes. •FDA approved for treatment of relapsed or refractory, low-grade or follicular, CD20 positive, B-cell non-Hodgkin’s lymphoma (NHL). 2/10/06: FDA approved for use in firstline treatment of patients with diffuse large B-cell, CD20 positive non-Hodgkin’s lymphoma, in combination with CHOP) cyclophosphamide, doxorubicin, vincristin and prednisone) or other anthracycline-based chemotherapy regimen. •In Phase III trials for treatment of relapsed chronic lymphocytic leukemia. •Also in development for treatment of certain inflammatory disorders.
Genentech and Roche	Herceptin (trastuzumab)		On the market (Metastatic breast cancer) Preparing filing for additional breast cancer indications		•Humanized monoclonal antibody that targets human epidermal growth factor receptor 2 protein (HER2). •FDA approved 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). •Genentech is preparing the FDA filing to seek approval for adjuvant breast cancer, and for use in combination with Taxotere for treatment of metastatic breast cancer.
Genentech and Roche	Omnitarg (pertuzumab)		Phase II		•Monoclonal antibody that is the first in a new class of therapies called HER dimerization inhibitors (HDIs). It blocks the ability of the HER2 receptor to collaborate with other HER receptor family members (HER1/EGFR, HER3, and HER4). •In Phase II in combination with chemotherapy for treatment of platinum-resistant ovarian cancer. •Also in Phase II development for metastatic breast cancer.
GenMab	HuMax-CD20 (ofatumumab)		Phase III		•For chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma
GenMab	HuMax-EGRf (zalutumumab)		Phase III		•For head and neck cancer •Phase I/II for head and neck cancer front-line
Genzyme	Campath (alemtuzumab)		On the market Phase III planned for multiple sclerosis In clinical trials for additional indications		•Humanized monoclonal antibody that targets the antigen CD52. •FDA approved for treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients who have been treated with alkylating agents and who have failed fludarabine therapy. •In clinical trials for additional indications including treatment of early active relapsing remitting multiple sclerosis, and also relapsing or refractory NHL.
ImClone Systems and Bristol-Myers Squibb and Merck KGaA	Erbitux (cetuximab)		On the market ( U.S. , Europe ) (colorectal cancer) Also approved in Switzerland for head and neck cancer In clinical trials for additional cancers (see comments)		•Chimeric (human/mouse) monoclonal antibody that targets the extracellular domain of the human epidermal growth factor receptor (EGFR, also called HER1, c-ErbB-1). •Originally developed by ImClone Systems, Erbitux is marketed by Bristol-Myers Squibb in the U.S. and by Merck KGaA outside the U.S. and Canada . •FDA approved 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. •In Phase III trials for treatment of earlier stage colorectal cancer, non-small cell lung cancer, head and neck cancer, and pancreatic cancer. In Phase II trials for additional indications. • US sales of Erbitux in 2005 were $413.1 million.
ImClone Systems	CDP-791		Phase II		•A PEGylated diFab antibody •Targets VEGFR-2.
Immunomedics	epratuzumab (IMMU-103)		Phase III (systemic lupus erythematosus[SLE]) Phase II (NHL and Sjögren’s syndrome)		•Humanized monoclonal antibody that targets CD22, found on the cell surface of B-lymphocytes. •In Phase III for treatment of SLE, Phase II for NHL, and Phase II for Sjögren’s syndrome.
Medarex and Bristol-Myers Squibb	MDX-010 (ipilimumab)		Phase III		•Fully human antibody that targets the CTLA-4 receptor •In Phase III trial in combination with MDX-1379 (a melanoma peptide vaccine) for treatment of melanoma. Also in clinical trials evaluating MDX-010 plus/minus chemotherapy for melanoma, and MDX-010 plus melanoma peptides for treatment of melanoma. •In Phase II studies as a monotherapy and in combination with Taxotere (docetaxel) for prostrate cancer. •In Phase II trial for breast cancer.
Medarex	MDX-060		Phase II		•Human monoclonal antibody that targets CD30. •For treatment of CD30 positive lymphomas including CD30 positive Hodgkin’s disease, anaplastic large cell lymphoma, and other CD30 positive cancers.
Medarex	MDX-070		Phase II		•Human monoclonal antibody that targets prostate specific membrane antigen (PMSA) •For treatment of prostate cancer
Merck KGaA ( Germany ) and EMD Pharmaceuticals (US)	matuzumab (EMD 72000)		Phase II		•Humanized monoclonal antibody targeted toward epidermal growth factor receptor (EGFR) •Being evaluated in clinical trials for cervical, ovarian, gastric, and lung cancers.
Pfizer and Abgenix	CP-675,206		Phase II		•Anti-CTLA-4 antibody •An immunomodulator that boosts the immune system response. •In Phase II for melanoma
Roche	CAL		Phase II		•Humanized anti-PTHrP monoclonal antibody •For humoral hypercalcemia of malignancy
Seattle Genetics	SGN-30		Phase II		•Monoclonal antibody targeted to the CD30 antigen. •In Phase II development for treatment of systemic anaplastic large cell lymphoma, cutaneous anaplastic large cell lymphoma, and Hodgkin’s disease.
Serono and Genmab	HuMax-CD-4 (zanolimumab)		Phase III		•Human antibody targeting the CD4 receptor •In Phase III for cutaneous T-cell lymphoma (CTCL), and in Phase II for non-cutaneous T-cell lymphoma.
Serono	adecatumumab (Previously called MT201)		Phase II		•Human monoclonal antibody targeting the epithelial cell adhesion molecule (Ep-CAM). •In Phase II trials for breast and prostate cancer. •12/04: Announcement that Serono signed an exclusive collaboration and licensing agreement with Micromet, gaining access to MT201.
United Therapeutics	OvaRex (oregovomab)		Phase III		•Monoclonal antibody that targets CA125, an ovarian cancer tumor marker. •OvaRex induces an immune response against CA125, and therefore against the ovarian cancer.
YM Bioscience ( Canada ) and Innogene Kalbiotech Ltd. ( Singapore )	nimotuzumab (TheraCIM hR3)		Phase II		•Humanized monoclonal antibody that targets the epidermal growth factor receptor (EGFR) •Phase II complete for head and neck cancer, and (as a monotherapy) for pediatric brain cancer. Phase II ongoing for metastatic pancreatic cancer. Phase III trial planned for adult glioma and Phase II planned for non-small cell lung cancer. •Partner: Innogene Kalbiotech Ltd. of Singapore .
Immune-Related Diseases
Abbott Laboratories		Humira (adalimumab)		On the market Submitted for approval (EU and US) for ankylosing spondylitis	•Recombinant human immunoglobulin G1 monoclonal antibody targeting human tumor necrosis factor (TNF). •FDA approved for treatment of adults with rheumatoid arthritis and psoriatic arthritis. •10/05: Announced that Abbott submitted for approval of Humira in EU and US for treatment of ankylosing spondylitis. •Also being evaluated in clinical trials for treatment of Crohn’s disease. •Abbott reports that Humira sales in 2005 were $1.4 billion worldwide (a 64.4% increase over 2004).
Abbott Laboratories		ABT-874		In clinical trials	•Fully human monoclonal antibody that targets IL-12 •Being evaluated for treatment of multiple sclerosis, psoriasis, and Crohn’s disease.
Amgen		denosumab (Formerly called AMG 162)		Phase III	•Human monoclonal antibody that targets the receptor activity of nuclear factor B ligand (RANKL) •In Phase III for bone loss induced by hormone ablation therapy for breast or prostate cancer, and for postmenopausal osteoporosis. •In Phase II for rheumatoid arthritis and for bone metastases
Amgen		AMG 108		Phase II	•Monoclonal antibody that blocks IL-1 activity •In Phase II for rheumatoid arthritis
Amgen and Genmab		AMG 714		Phase II	•Human monoclonal antibody directed against IL-15 •In Phase II for treatment of rheumatoid arthritis •Partner: Genmab
Biogen Idec and Elan		Tysabri (natalizumab)		sBLA submitted to FDA 9/05	•Humanized monoclonal antibody that binds to alpha4-integrin. •Originally approved for multiple sclerosis, but marketing and ongoing clinical trials were suspended in 2/05 following cases of progressive multifocal leukoencephalopathy (PML). •Following a safety evaluation, an sBLA was submitted to the FDA in 9/05 for multiple sclerosis. •FDA approves reintroduction for treatment of relapsing forms of multiple sclerosis in 6/06. •In Phase III studies for rheumatoid arthritis and Crohn’s disease. •2/06: Announcement that the FDA had removed the hold on clinical trial dosing of TYSABRI in multiple sclerosis in the U.S.
Biogen Idec and PDL BioPharma		HuZAF (fontolizumab)		Phase II	•Humanized anti-interferon gamma antibody •For treatment of inflammatory disorders. •Originally developed by Protein Design Labs (now PDL BioPharm). In 8/05, Biogen Idec and Protein Design Labs announced a collaboration that included HuZAF.
Biogen Idec and PDL BioPharma		Daclizumab (anti-CD25)		Phase II (multiple sclerosis) (See also status under PDL BioPharma and Roche)	•Humanized monoclonal antibody targeted to the CD25 antigen •In Phase II trial in patients with multiple sclerosis. •Marketed by Roche under the trade name Zenapax for prevention of renal allograft rejection. •PDL BioPharma has completed a Phase II trial of daclizumab in asthma. •PDL BioPharma has exclusive worldwide rights for Zenapax. •Originally developed by Protein Design Labs (now PDL BioPharma). In 8/05, Biogen Idec and Protein Design Labs announced a collaboration that included daclizumab.
Centocor (Johnson & Johnson) Marketed by Schering-Plough internationally		Remicade (infliximab)		On the market Filed for approval (juvenile rheumatoid arthritis and psoriasis) Phase III (pediatric Crohn’s)	•Chimeric monoclonal antibody targeted against human TNF-alpha. •FDA approved for treatment of rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, psoriatic arthritis, and ulcerative colitis •Filed for approval for treatment of juvenile rheumatoid arthritis and psoriasis. In Phase III clinical trials for pediatric Crohn’s disease • Recommended for approval in EU for treatment of moderately to severely active ulcerative colitis. •J&J reports Remicade sales worldwide in 2004 were $2.145 billion. •Schering-Plough reports Remicade sales of $746 million for 2004.
Centocor (Johnson & Johnson) and Schering-Plough		CNTO 148 (golimumab)		Phase III	•Human monoclonal antibody targeted to TNF-alpha. •For treatment of inflammatory diseases including Crohn’s disease, rheumatoid arthritis, and uveitis. •Results of a Phase II trial in patients with rheumatoid arthritis announced 11/05. •Antibody developed by Medarex.
Centocor (Johnson & Johnson)		CNTO 1275		Phase III	•Human monoclonal antibody targeted to interleukin (IL)-12 and IL-23. •For treatment of inflammation. •Antibody developed by Medarex.
Genentech and Roche and Biogen Idec		Rituxan/MabThera (rituximab)		Submitted to FDA (rheumatoid arthritis) On the market (NHL)	•Chimeric monoclonal antibody targeted against the CD20 antigen on the surface of B lymphocytes. •FDA approved for treatment of relapsed or refractory CD20 positive, B-cell NHL. •Submitted to FDA for treatment of rheumatoid arthritis in patients who do not respond adequately to anti-TNF therapy. •In Phase III clinical trials for treatment of DMARD refractory rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. •Also in clinical trials for additional hematological cancers.
Genentech and Roche		ocrelizumab		Phase II	•Fully humanized anti-CD20 antibody – Second-generation anti-CD20 •In Phase II for rheumatoid arthritis
Genmab		HuMax-CD20		Phase II (Rheumatoid arthritis)	•Human monoclonal antibody targeted against the CD20 antigen on B cells. •In Phase II for rheumatoid arthritis, and Phase I/II for non-Hodgkin’s lymphoma and chronic lymphocytic leukemia.
Genzyme		Campath (alemtuzumab)		On the market (CLL) Phase III trial on hold for multiple sclerosis	•Humanized monoclonal antibody that targets the antigen CD52. •FDA approved for treatment of B-CLL in patients who have been treated with alkylating agents and who have failed fludarabine therapy. •In clinical trials for additional indications including treatment of early active relapsing remitting multiple sclerosis, and also relapsing or refractory NHL.
Human Genome Sciences and GlaxoSmithKline		LymphoStat-B (belimumab)		Phase II	•Human monoclonal antibody that inhibits B-lymphocyte stimulator (BlyS). •Phase II results reported for rheumatoid arthritis; Phase II results in serologically active systemic lupus erythematosus: (SLE) reduced disease activity. •Plan to initiate Phase III before end of 2006 •In development for treatment of rheumatoid arthritis, SLE, and other autoimmune diseases.
Immunomedics		epratuzumab (IMMU-103)		Phase III (SLE) Phase II (NHL and Sjögren’s syndrome)	•Humanized monoclonal antibody that targets CD22 (which is found on the cell surface of B-lymphocytes). •In Phase III for treatment of SLE, Phase II for NHL, and Phase II for Sjögren’s syndrome.
Millennium Pharmaceuticals		MLN1202		Phase II	•Humanized monoclonal antibody that targets the CCR2 chemokine receptors •In Phase II trials for multiple sclerosis,and atherosclerosis.
PDL BioPharma		Visilizumab (Nuvion)		Phase II/III	•Humanized monoclonal antibody targeted to the CD3 antigen on the surface of T lymphocytes. •In Phase II/III for IV steroid-refractory ulcerative colitis and in Phase I for Crohn’s disease
PDL BioPharma		Daclizumab (anti-CD25)		Phase II (multiple sclerosis) Phase II complete (asthma) On the market (prevention of renal allograft rejection)	•Humanized monoclonal antibody targeted to the CD25 antigen. Composite antibody with 90% human and 10% murine sequences. •Marketed by Roche under the trade name Zenapax for prevention of renal allograft rejection. •PDL BioPharma has exclusive worldwide rights for Zenapax for all disease indications other than prevention of organ transplantation. Roche discontinued joint development and commercialization agreement for long-term maintenance therapy following organ transplantation in 11/06 •Originally developed by Protein Design Labs (now PDL BioPharma). In 8/05, Biogen Idec and Protein Design Labs announced a collaboration that included daclizumab.
Roche		Actemra (tocilizumab) (R1569)		Phase III	•Humanized anti-IL-6 receptor monoclonal antibody •For rheumatoid arthritis and systemic juvenile idiopathic arthritis •Being developed jointly with Chugai.
Roche		ocrerlizumab (R1594)		Phase II	•Humanized anti-CD20 monoclonal antibody •For rheumatoid arthritis
UCB (Formerly Celltech)		certolizumab pegol (CDP870)		Phase III	•Pegylated Fab fragment of a humanized anti-TNF-alpha monoclonal antibody. •In Phase III trials for treatment of Crohn’s disease and rheumatoid arthritis.
Other
Alexion Pharmaceuticals		Soliris (eculizumab)		Phase III	•Monoclonal antibody that binds the C5 complement protein and blocks complement activation by blocking cleavage of the C5 protein. •1/06: Alexion announced positive Phase III results evaluating eculizumab for treatment of paroxysmal nocturnal hemoglobinuria (PNH). •Phase II trials have been completed for rheumatoid arthritis and membranous nephritis. There appears to be no current development activity in these areas. •In preclinical development for transplantation and asthma.
Alexion Pharmaceuticals and Procter & Gamble		pexelizumab		Phase III	•Monoclonal antibody that is a C5 complement inhibitor. •Currently in Phase III development for acute myocardial infarction. •11/05: Alexion announced that a Phase III trial in coronary artery bypass graft (CABG) patients failed to meet the primary endpoint.
Centocor (Johnson & Johnson)		ReoPro (abciximab)		On the market Phase III for facilitated percutaneous coronary intervention	•Fab fragment of a chimeric monoclonal antibody that targets the glycoprotein (GP) II/IIIa receptor on human platelets. ReoPro also binds to the vitronectin (alpha v beta 3) receptor. •Blocks platelet aggregation. •FDA approved 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 are not responding to conventional therapy when percutaneous coronary intervention is planned within 24 hours. •In Phase III for facilitated percutaneous coronary intervention. •Was being evaluated in clinical trials for ischemic stroke. The trials were temporarily suspended in 9/05, and permanently discontinued in 10/05 following a review of safety concern and the benefit-risk profile.
Genentech and Novartis and Tanox and Roche (through Genentech)		Xolair (omalizumab)		On the market (asthma) Phase III (peanut allergy)	•Humanized monoclonal antibody that targets IgE •FDA approved for treatment of adults and adolescents with moderate to severe persistent asthma •In Phase III development for pediatric asthma and in Phase II for peanut allergy.
Genentech		Raptiva (efalizumab)		On the market Preparing for Phase II for adult atopic dermatitis	•Humanized monoclonal antibody that targets CD11a, which is the alpha subunit of leukocyte function antigen-1 (LFA-1). •FDA approved for treatment of adults with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. •Genentech is preparing to start a Phase II trial evaluating Raptiva for treatment of adult atopic dermatitis.
GlaxoSmithKline		mepolizumab		Phase III	•Anti-IL-5 monoclonal antibody •In Phase III for hypereosinophilic syndrome and osinophilic esophagitis. •In Phase II for asthma and nasal polyposis
Tanox (acquired by Genentech 11/06)		TNX-355		Phase II	•Human monoclonal antibody that binds to the CD4 receptor, thus preventing entry of HIV into the cell. •For treatment of HIV/AIDS
Wyeth		MYO-029		Phase I/II	•Recombinant human antibody that binds to and inhibits the activity of myostatin (growth and differentiation factor 8, or GDF-8). •For treatment of muscular dystrophy