Neil W Gibson of OSI Pharmaceuticals

Jeffrey Settleman,  Harvard Medical School and MGH Cancer Center

David Bailey of Chemoventures

N Claude Cohen of Synergix

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The Evolving Market for Monoclonal Antibodies: Facing New Opportunities and Pitfalls

By Lucy Sannes, Ph.D., President, Sannes and Associates, and Malorye A. Branca, Editor-in-Chief, PharmaWeek

Most importantly, while antibodies were once of interest primarily to smaller biotechnology companies, these products have clearly garnered the attention of large pharmaceutical companies as well.  Last year, Roche netted a neat $6 billion off of antibodies, all through its deals with Genentech.  Today, most large companies want some piece of the flourishing antibody market. 

At the same time, antibodies are expensive to make, and payers are beginning to balk at huge bills for drugs that have modest effects.  Some clinics in Britain, for example, are refusing to prescribe Genentech/Roche's Herceptin (trastuzumab) for early stage breast cancer, despite the fact that leading oncologists have described the drug's effects in this population as "revolutionary."  (See Hortobagyi, G, NEJM, Oct. 20, 2005).  Now, the high price tag of Avastin (also from Genentech) is generating similar resistance from payers. Patients and doctors, meanwhile, are increasingly asking, "Why do these drugs have to cost so much?"

It's also become clear that MAbs also have their drawbacks. The recent (possibly temporary) withdrawal of Biogen Idec's Tysabri (natalizumab) and the cardiac effects seen in some patients receiving Herceptin have brought attention to these concerns.  (For more on Herceptin and the heart, see Chien, K, NEJM, Feb. 23, 2006)

The market for MAbs thus holds tremendous promise but great uncertainty as well. It's easy to be impressed by today's blockbuster MAbs, but as a wave of new products spills onto the market, success will be determined by an increasing number of factors.

 A Long Road

Not surprisingly, all was not rosy on the path to success for these drugs. Today, developers of other platform technologies such as antisense, gene therapy, and stem cells like to point to the many difficulties, and long wait, that characterized the development history of the first MAbs. Despite serious setbacks and huge costs, companies had to stick with the technology to reach the tremendously rewarding phase they are now enjoying.

Researchers have been investigating antibodies as potential therapeutic agents for more than a century. One of the biggest advances in the use of antibodies to treat disease occurred in 1975 when Georges Köhler and Cesar Milstein discovered that MAbs can be produced by hybridoma cells—hybrid cells that are formed by the fusion of an antibody-secreting murine lymphocyte cell with a murine myeloma cell. With this discovery, there was considerable hope (and hype) that MAbs would soon become a reality for human therapeutics.

Yet, it was 11 years before the first MAb therapy reached the market (Ortho Biotech's Orthoclone OKT3, muromonab-CD3) and another 8 years until the FDA approved the second antibody-based therapy (Centocor's ReoPro, abciximab). Thus, 20 years after the discovery of the process to make MAbs, only two MAb-based therapies had reached the market in the United States.

Now, more than 30 years after Köhler's and Milstein's discovery, this field has progressed dramatically, and MAb-based therapies have proven to be major clinical and marketing successes. (See Table 1 for currently marketed antibodies.) 

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 First FDA-Approved
Ortho Biotech(Johnson & Johnson)	Orthoclone OKT3(muromonab-CD3)	NA	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  (for 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 are not responding to conventional therapy when percutaneous coronary intervention is planned within 24 hours.	1994
Genentech and Roche and 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:  FDA approved for use in first-line treatment of patients with diffuse large B-cell, CD20 positive NHL, in combination with CHOP (cyclo-phosphamide, doxorubicin, vincristine,  and prednisone) or other anthracycline-based chemotherapy regimen.	1997
Hoffmann-La Roche	Zenapax(daclizumab)	NA	IL2 receptor	Humanized	For prophylaxis of acute organ rejection in renal transplant patients.	1997
Novartis	Simulect(basiliximab)	NA	IL2 receptor	Chimeric	For prophylaxis of acute organ rejection in renal transplant patients when used as part of an immuno-suppressive 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 U.S., 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)	NA	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 U.S., Berlex Laboratories in U.S.)	Campath(alemtuzumab)	NA	CD52	Humanized	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.	2001
Biogen Idec(marketed by Schering AG outside the U.S.)	Zevalin(ibritumomab tiuxetan)	$18.7(U.S. 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 and Novartis and Tanox and Roche (through Genentech)	Xolair(omalizumab)	$321 (U.S. 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 (U.S. 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 and Bristol-Myers Squibb and Merck KgaA	Erbitux (cetuximab)	$413 (U.S. 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 for patients with metastatic colon cancer or rectum cancer.	2004

 NA = Not available.

Source:  Sannes & Associates, Inc.

Building Mouse-Based MAbs

The first MAbs were murine antibodies, which have been used successfully for in vitro diagnostic applications (in which the antibodies are used in a clinical laboratory to detect antigens or antibodies in a patient's serum or other body fluids). However, when murine antibodies are injected into a patient, the immune system identifies them as foreign proteins, and a human antimouse antibody (HAMA) response often occurs.

This response can cause an allergic reaction in some patients and, if the reaction is severe, can result in death. In an effort to reduce this HAMA response, many approaches have been developed to genetically engineer antibodies. An early strategy was to develop 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, humanized antibodies were developed. In these antibodies, only the complement-determining region (CDR) is retained from the murine antibody, and the rest of the antibody is human. More recently, some companies have developed methods to generate fully human MAbs. Other approaches, including the use of antibody fragments, have also been used.

The Age of Human/Humanized Antibodies

The first two antibodies to reach the market in the United States were murine and chimeric, respectively, and some additional such products have since been approved in the United States. 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. (Table 2, at the end of this article, lists MAb-based drugs in later stages of development.)

MAbs can be used to treat a wide range of diseases, but one area where they have already made a huge impact is cancer—including both solid tumors and hematological malignancies.

Eight of the antibodies on the market in the United States today are approved for cancers, and these products include three of the six antibodies that had more than $1 billion in sales each in 2005. Genentech developed all three of these blockbusters, and they are marketed by that company in the United States and Roche in the rest of the world. They include Rituxan (rituximab, marketed as MabThera outside the United States) for treatment of non-Hodgkin's lymphoma, Herceptin (trastuzumab) for treatment of breast cancer, and Avastin (bevacizumab) for treatment of metastatic colorectal cancer. These three antibodies are included among Roche's five top-selling pharmaceutical products and had combined sales of greater than $6 billion worldwide in 2005.

These Genentech/Roche antibodies, and most of the MAbs on the market or in late-stage development for treatment of cancer, are naked (or unconjugated) antibodies that function by targeting proteins associated with the cancer. For example, Herceptin blocks a growth factor receptor (HER2) that is overexpressed in some breast cancers, Rituxan targets an antigen (CD22) that is found on certain lymphoma cells, and Avastin inhibits angiogenesis by targeting vascular endothelial growth factor (VEGF).

This approach of using unconjugated antibodies clearly can succeed in both the clinic and the market, and many other companies are pursuing this approach. Unconjugated MAbs in Phase III development for treatment of cancer include:

• Amgen's panitumumab (targeting epidermal growth factor receptor, or EGFR)
• Immunomedics' epratuzumab (targeting CD22)
• Bristol-Myers Squibb's/Medarex's MDX-010 (targeting the CTLA-4 receptor), Serono/Genmab's zanolimumab (targeting the CD4 receptor)
• United Therapeutics' oregovomab (targeting CA125).  

These late-stage antibodies demonstrate the wide range of proteins and cancers that can be targeted by MAbs for treatment of cancer. Even more antibodies that have reached Phase II development for cancer are listed in Table 2.

Increasing the Killing Quotient Through Conjugates

An alternative strategy for using MAbs to treat cancer is to use the antibody for targeted delivery of a cytotoxic drug or radioactive isotope to the site of the cancer. In 2000, the first therapeutic antibody conjugated to a cytotoxic drug (Wyeth's Mylotarg) received FDA approval. Mylotarg is a humanized antibody that is conjugated to the cytotoxic antitumor antibiotic calicheamicin. It is approved for treatment of CD33-positive acute myeloid leukemia (AML). Currently, Mylotarg is the only antibody conjugated to a cytotoxic drug that is available in the United States, and no antibodies delivering cytotoxic drugs appear to be in late-stage clinical development.

An alternative strategy is to use MAbs for targeted delivery of toxins to cancer cells. At this time, no immunotoxins have reached the market. However, Cambridge Antibody Technology's CAT-3888 is in Phase II development for hairy cell leukemia and 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 ones from ImmunoGen, are in earlier-stage development.

While most are still in early stages of development, conjugated MAbs are attracting a lot of attention.  One advantage is that previously proven products could be enhanced with new "payloads." Genentech is already investigating whether Herceptin (trastuzumab) is even more powerful when tied to a microtubule function inhibitor, DM1 (maytansinoid). Preclinical studies have shown that the company's trastuzumab-DM1 conjugate not only inhibits and suppresses tumor growth, but it also causes tumor cell death by delivering DM1 into these cells. The conjugate seems to affect only tumor cells which express high levels of HER2.

Advantages and Limitations of Radioimmunotherapy

For radioimmunotherapy, the two most commonly used radioisotopes are iodine (I-131) and yttrium-90 (Y-90). Both are high-energy beta emitter isotopes. The range of these beta particles extends beyond the cell targeted by the antibody, so they can also kill surrounding antigen-negative cells. This could enhance the therapeutic efficacy of the antibody compared with an unlabeled antibody.

Two radioimmunotherapies have received approval in the United States. The first radioimmunotherapy to reach the U.S. market was Zevalin (ibritumomab tiuxetan; Biogen Idec), which was approved in 2002 for treatment of non-Hodgkin's lymphoma (NHL). Zevalin is a murine MAb targeted against the CD20 antigen. The Zevalin kit contains materials for preparation of both indium-111 Zevalin (for imaging) and yttrium-90 Zevalin (for therapy). Zevalin is administered 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 this radiotherapy product were $18.7 million, compared with $19.6 million in 2003.

A second radioimmunotherapy, Bexxar, was approved in 2003, also for treatment of NHL. Bexxar is an I-131-labeled antibody. Sales of this agent have also been limited. Bexxar was originally developed by Corixa. In December 2004, Corixa 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 it.

While radioimmunotherapy represents a potentially promising strategy for treatment of cancer, this approach also has its disadvantages. With the addition of the radioisotope and the requirement for a hospital to obtain the isotope and label the antibody, this approach is not as simple as using unconjugated antibodies (which are proving to be effective for many patients). Also, there are disadvantages associated with the use of radioisotopes. I-131 is readily available, and it is relatively easy to label antibodies with I-131. However, it has a relatively long half-life (8 days), and dehalogenation of the isotope from the antibody can occur and result in thyroid damage by the radioactive iodine. 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 binding the antibody because Y-90 is retained in the cell. However, Y-90 is incorporated into bone and can thus result in higher radiation doses to bone marrow than those resulting from I-131.

While radioimmunotherapy products can clearly demonstrate efficacy and reach the market, the commercial success of radioimmunotherapy has yet to be demonstrated. Additional radioimmunotherapies are being evaluated, but they are all in early stages of development.

Targeting Immune Disease and Other Indications

A second major therapeutic area in which MAbs have demonstrated both clinical and commercial success is immune-related diseases. These diseases include autoimmune diseases, inflammation, and immune suppression (for prevention of rejection following transplants). Two "blockbuster" MAbs, with annual sales that exceed $1 billion each, targeting the immune system are Centocor's Remicade (infliximab) and Abbott's Humira (adalimumab). Both of these drugs target tumor necrosis factor alpha (TNF-alpha), although Remicade is a chimeric antibody and Humira is a human antibody. Remicade is indicated for treatment of rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, and ulcerative colitis. Humira is indicated for treatment of rheumatoid arthritis and psoriatic arthritis. Both of these antibodies compete against Amgen's Enbrel (etanercept), which is not a true MAb. It is a fusion protein that consists of the extracellular ligand-binding portion of tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1.

These and other MAbs for treatment of immune-related diseases are presented in Table 1. In addition, more than 20 MAbs are in Phase II or Phase III clinical trials for treatment of a range of immune-related disorders (see Table 2).

In addition to cancer and immune-related diseases, MAbs can be used to treat a wide range 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 is used for a cardiovascular application. Additional antibodies in late-stage development for various indications are included in Table 2.

One notable MAb is Biogen Idec's and Elan's Tysabri, which was approved by the FDA but was later withdrawn from the market owing to safety concerns following reports of progressive multifocal leukoencephalopathy (PML). In February 2006, the FDA removed the hold on clinical trial dosing of Tysabri in multiple sclerosis in the United States. The companies resubmitted this antibody to the FDA in September 2005, and it was subsequently granted priority review. Tysabri is scheduled to be reviewed by an FDA advisory committee in March 2006 and may reach the market again.  This drug brought great hope and anticipation to the public and physicians and the PML cases were a serious setback that re-enforced how difficult it can be to both fully understand a drug's effects and to isolate the causes of conditions that affect seriously ill patients.

MAbs now represent a large, well-established market that continues to grow dramatically each year. Antibodies currently on the market in the United States had global sales of greater than $13 billion in 2005. Growth in this market is being fueled by continuing increases in the sales of current products (especially the blockbuster products) as well as the introduction of new therapeutic antibodies.

As demonstrated in Table 2, more than 40 new MAbs are in Phase II or later development. These do not include those antibodies already on the market which are now being developed for additional indications. In addition to the MAbs listed in Tables 1 and 2, many more are in earlier clinical or preclinical development.

Clash of the Titans?

Another example of the importance of therapeutic MAbs is Amgen's December 2005 announcement that it had agreed to acquire Abgenix for approximately $2.2 billion in cash plus assumption of debt. With this acquisition, Amgen will acquire full rights to panitumumab (a human antibody in Phase III development) plus Abgenix's technology for producing human antibodies.

So far, Genentech has been the undisputed leader in antibody development. But a growing number of companies, including Amgen, are starting to see antibodies as an essential part of any big pipeline. For example, Novartis has recently made a substantive investment in developing its own antibody expertise, mainly through its collaborations with MorphoSys. As more companies get involved in this field, the competition to develop the best MAb-based drugs is likely to heat up. In addition, because they are so targeted, MAbs are ideal products to combine with other drugs to maximize their effects. It is thus likely that the MAb market will continue to grow dramatically over the next few years and that more of these drugs will become blockbusters.

As pointed out, pricing is becoming an increasingly important topic for antibody developers. The cost of drugs in general is a growing concern, as countries try to cut their health care bills, but MAbs have become emblematic of the problem.  In addition, the withdrawal of Tysabri sent a shockwave through the industry: While these drugs are very specific, hitting their targets with great precision, that doesn't mean that they are without side effects.  It is clear that many of these targets have roles in multiple cellular and physiological processes.

Getting a MAb on the market is thus not a slam dunk.  Developers of these drugs will face increasing competition, both from other MAb makers and new other platforms, as well as greater scrutiny from regulators and payers. Careful target and indication selection will be the hallmarks of future success in this field.  While there is certain to be another wave of very successful products, it's less clear where those will come from, as new entrants gear up. In addition, there is likely to be an increasing number of products that will make it to market but which will not reap as great a reward as anticipated, either because of payer reluctance or because other products simply work better.

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

 

Company	Product		Phase			Comments
Cancer
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		Phase II			For non-Hodgkin's B-cell lymphoma
Biogen Idec	Anti-CD23 MAb		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 rectum 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 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 first-line treatment of patients with diffuse, large B-cell, CD20-positive NHL, in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or other anthracycline-based chemotherapy regimen. ïIn 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.
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. U.S. 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 (SLE) Phase II (NHL and Sjogren's syndrome)			Humanized monoclonal antibody that targets CD22 (which is found on the cell surface of B-lymphocytes). In Phase III for treatment of systemic lupus erythematosus (SLE), Phase II for NHL, and Phase II for Sjogren's syndrome.
Medarex and Bristol-Myers Squibb	MDX-010		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 prostate 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 (PSMA). For treatment of prostate cancer
Merck KGaA (Germany) and EMD Pharmaceuticals (U.S.)	matuzumab (EMD 72000)		Phase II			Humanized monoclonal antibody targeted towards 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			Anti-PTHrP monoclonal antibody. For bone metastases.
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 cancers. 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)	nimotuzumab (TheraCIM hR3)		Phase II			Humanized monoclonal antibody that targets the 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 of Singapore.
Immune-Related Diseases
Abbott Laboratories		Humira (adalimumab)		On the market   Submitted for approval (E.U. and U.S.) for ankylosing spondylitis	Recombinant human IgG1 monoclonal antibody targeted against human TNF. FDA approved for treatment of adults with rheumatoid arthritis and psoriatic arthritis. 10/05:  Announced that Abbott sought approval of Humira in E.U. and U.S. 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 osteoarthritis.
Amgen		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   FDA advisory committee meeting scheduled for 3/7/06	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, a supplemental biologic license application (sBLA) was submitted to the FDA in 9/05 for multiple sclerosis. 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 for all disease indications other than organ transplantation. 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. Recommended for approval in E.U. 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 II	Human monoclonal antibody targeted to tumor necrosis factor alpha (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 II	Human monoclonal antibody targeted to interleukin-12 (IL-12) and IL-23. Being evaluated in a Phase II trial 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 disease-modifying anti-rheumatic drug (DMARD)-refractory rheumatoid arthritis, SLE, 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 NHL and chronic lymphocytic leukemia.
Genzyme		Campath(alemtuzumab)		On the market (CLL) Phase III planned for multiple sclerosis	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.
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. In development for treatment of rheumatoid arthritis, SLE, and other autoimmune diseases.
Immunomedics		epratuzumab(IMMU-103)		Phase III(SLE) Phase II (NHL and Sjogren'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 Sjogren's syndrome.
Millennium Pharmaceuticals		MLN1202		Phase II	Humanized monoclonal antibody that targets the CCR2 chemokine receptors. In Phase II trials for rheumatoid arthritis, 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. Marketed by Roche under the trade name Zenapax for prevention of renal allograft rejection.