MONOCLONAL ANTIBODIES

Companies all across the world are in pursuit of tapping the booming monoclonal antibodies market (mAbs). Between 2005 and 2008, the market  witnessed an exponential growth wherein the global mAbs market more than quadrupled in just four years from Rs 31,101 crore ($7 bn) in 2004 to Rs 1.55 lakh crore ($35 bn) in 2008 with the ‘Big Four’-Roche, Genentech (now a subsidiary of Roche) , Johnson & Johnson and Abbot leading the race. Therapeutic mAbs market is dominated by the ‘Big Five’ products-Avastin and Herceptin for oncology); Humira and Remicade for autoimmune and infectious disease (AIID); and Rituxan for oncology and AIID. In 2006, these products accounted for 80 percent of the revenues with Roche-Genetech owning three of these products.Industry experts are optimistic about the mAbs segment, which is expected to touch a compound annual growth rate (CAGR) of 14 percent between 2006 and 2012, surpassing growth rate of 0.6 percent in the more traditional, small molecules market. Dr Rustom Mody, chief scientific officer and director – quality, Intas Biopharmaceuticals, includes the Rs 44,430 crore ($10 bn) sales of mAbs for diagnosis and as reagents in research, so the market is worth Rs 2.22 lakh crore ($50 bn).The boom in the mAbs segment is due to the increasing popularity of targeted therapeutic mechanism approaches among scientific community, particularly in disease segments like oncology and AIID. In case of cancer, conventional treatment of chemotherapy and radiation therapy, it often results in relapse and such patients ultimately die either from their cancer or due to toxicity levels of the therapy. The development of mAbs for these disorders have been studied to improve the therapies and minimize the toxicities associated with standard therapies. MAbs are designed to demonstrate efficacy with low toxicity and are expected to reduce overall treatment and hospitalization costs associated with the side effects and opportunistic infections, which can result from chemotherapy or radiation therapy.According to an independent market analyst, Datamonitor, with key individual mAb product franchises forecast to record peak sales growth through broadening horizontal indication  and the launch of new products in the next few years, this rapid expansion is expected to continue. The commercial dominance of the big five is expected to continue till 2012, with the same products forecast to account for 70 percent of 2012 mAbs revenues. Datamonitor  also predicts that Genentech/Roche will retain their dominance over the mAbs market till 2012, due to their ownership of three of the big five products. Oncology and AIID will remain the main focus areas for mAbs segment as they are the disease areas addressed by the ‘big five’.Industry analysts point out that new players such as Biogen Idec, Amgen, Novartis and UCB Pharma, Bristol-Myers Squibb and Sanofi-aventis will expand their presence in the mAbs market by 2012.

Growth demand for mAbs
With dwindling R&D pipelines, patent expiration of blockbuster products, and  apprehensions over subsequent dip in revenues till 2012, most pharmaceutical companies have chalked out a ‘mAbs strategy’. This was evident from a spate of licensing deals between pharma and biotech companies in the mAbs space and a  spree of biotech firms  being acquired by pure pharma companies in the recent past. In 2006, GSK etched a mark with the company licensing a drug for leukaemia from Genmab for Rs 9,341 crore ($2.1 bn), the largest ever deal in terms of value in the mAbs segment. The year 2009 saw some mega mergers with the Roche-Genentech deal gaining the center of attraction.

“MAbs offer an enormous amount of target specificity that reduces the nonspecific, untoward side effects commonly observed in small molecules. Many companies across the globe have mAbs products in advanced clinical trials stage,” says Dr Mody. Cancer and anti-infammatory segments contribute 51 and 30 percentages respectively, according to a report by Datamonitor and Frost & Sullivan.

Experts from the scientific community point out that human mAb has a higher rate of technical success and negligible levels of toxicity and lesser degrees of side effects. “The platform technology can easily be adapted for novel mAbs as the variability that can be introduced within the antigen-binding domains of mAbs increases their molecular diversity and extends the range of potential therapeutic applications,” says Dr Mody.

On the international front, numerous factors have motivated the companies to opt for mAbs. There has been an upsurge in demand for mAbs products because very few chemical-based products are available to provide effective cure for diseases such as cancer, asthma, anti-inflammatory, osteoporosis and opthalmology. “Chemical-based products have failed to provide remedy for oncology diseases. The technological competency of mAbs helps to get rid of these diseases,” says Sujay Shetty, associate director of pharmaceutical and lifesciences, PricewaterhouseCoopers India.

The commercial success of blockbuster products like Avastin and Herceptin for oncology; Humira and Remicade for AIID; and Rituxan for both oncology and AIID,  has been a stimulus for the companies rolling out a large number of R&D projects in mAbs. Remicade has been the best selling antibody since 2004 and was the market leader with sales of over Rs 28,915 crore ($6.5 bn) in 2008, followed by Rituxan, Avastin, Herceptin and Humira. The first three products made it to the top ten and all five products made it to the top 20 global best selling human medicinal brands. Till 2008, there were over 200 antibodies out of 630 biologics in clinical trials testing for cancer, arthritis, infections, asthma, macular degeneration, osteoporosis, diabetes and other chronic diseases. Increased sales and profitability have attracted mainstream pharmaceutical companies towards mAbs. The pressure of pricing is much lower in this space.

In India, the demand for mAbs is increasing and there is an upsurge in the number of Indian companies venturing into this space. India has capitalized on its so-called ‘low cost destination’ advantage. “Huge investment is needed to establish large scale manufacturing facilities for mAbs. The fund needed for setting up large scale operations is still lower in India as compared to developed markets. By establishing their operations in India those developed markets can fulfill their growing demand for mAbs products. India offers the possibility of improving their profit margins,” says Dr Mody . Biocon and Dr Reddy’s Labs, two of India’s top life sciences companies, have already launched their products in the market successfully.

The latest debate among  the biotech circles are the opportunities that biosimilar mAbs has to offer to companies. The global biosimilars market is primarily dominated by three main components – mAbs, therapeutic proteins and vaccines. In 2009, 29 mAbs were approved and marketed for therapeutic use. With the patent expiry of products like Herceptin, Humira and Rituxan by 2020, generic versions of these products are in the pipeline of many Indian players. Analysts  predict that it will be a  tussle for dollars for Indian players in the coming decade. Currently there are about 25 Indian companies  operating in the space bringing out at least 40 products in the market and many of them are well positioned to compete in the global mAbs landscape. “This product class is gaining maturity and within five years, when the second wave of biologicals are going to be off-patent, many of which are blockbuster mAbs, India is likely to dominate biosimilar mAbs development and manufacturing,” adds Dr Mody.

In terms of funding, venture capital firms are optimistic about mAbs space. “Globally, venture capitalists are willing to invest in two areas – interferons and mAbs,” says Shetty The main reason for this is the patent expiry of mAbs worth Rs 47,154 crore ($10.6 bn) by 2018. MAbs is the focus area for many pharma and non-pharma companies and hence R&D, M&A and licensing deals are happening in billion dollars for this class of products. A venture capitalist from a leading firm in India told BioSpectrum (without mentioning any names) that he  was aware of many reputed VC firms (which includes his firm) in India are looking at investing in mAbs space in the event of a rising number of Indian companies venturing into the segment.

mAbs in India
Biocon was the first Indian company to come up with its mAbs product, BIOMAb-EGFR, and the product was granted regulatory marketing and manufacturing approval in India in September 2006. The product is a therapeutic monoclonal antibody-based drug for treating solid tumors of epithelial origin, such as head and neck cancers. This novel drug is engineered to specifically target and block the epidermal growth factor receptor (EGFR) responsible for the proliferation of cancer cells. Dr Harish Iyer, R&D head, Biocon, “As far as Biocon’s portfolio is concerned, we have one product in the market from our stable.

BIOMAb EGFR (Nimotuzumab) is a monoclonal antibody that specifically binds to the extracellular domain of EGFR and prevents signal transduction. It is used in the treatment of advanced squamous cell carcinoma of the head and neck region with concurrent chemotherapy and/or radiotherapy.” It is also being globally studied in a range of solid tumor types, including colorectal cancer, lung cancer, glioma and pancreatic cancer. “Biocon has also partnered with Mylan for co-developing biosimilar mAbs. This is a co-development, cost sharing agreement for a bunch of molecules that are currently in development,” says  Dr Iyer.

Apart from being a low cost manufacturing destination, Indian companies have the upper hand of offering mAbs products at  comparatively lesser price margins. At the launch of BIOMAb -EGFR, Dr Kiran Mazumdar-Shaw, chairman and MD of Biocon, said, “BIOMAb -EGFR is competitively priced to make cancer treatment more affordable. “In 2007, Dr Reddy’s Labs came out with the novel concept of producing the biosimilar version of Rituximab, a version of Roche’s cancer therapy, which could allow a greater access to the drug at half the price of the original. With the more complex molecules like mAbs, Dr Reddy’s believes that the preferred strategy is to systematically develop the entire spectrum of development and manufacturing capabilities. The complexity of the molecules and the processes means a close integration of all the relevant skills within one organization with direct links between the manufacturing groups and the process, analytical, pre-clinical and clinical development groups. World-class facilities and laboratories of Dr Reddy’s, the scientific depth of its team, the robustness of the development strategy and the focus on quality issues were some of the key factors that contributed to the successful development of a complex molecule like Reditux.

Reditux is the second product from Dr Reddy’s Biologics Division, which is developing treatments for cancer and autoimmune diseases. The company has also launched the generic version of Amgen’s Neupogen, and named it Grafeel. The company has spent more than Rs  44.48 crore ($10 mn) for developing Reditux and within a year of its launch the products have successfully gained 30-35 percent share of the market. Dr Reddy’s Reditux is priced at Rs 39,996 for a vial and is almost half the price of Roche’s Mabthera. This product is now approved for marketing in India.

Pune-based Serum Institute has entered into another agreement with Akorn of the US in 2007  for definitive development and exclusive distribution rights for rabies mAb. As part of the agreement, Serum has agreed to appoint Akorn as the exclusive distributor for rabies mAb. In exchange for Akorn receiving the exclusive marketing and distribution rights of North, Central, and South America, Akorn has agreed to provide Serum funding for product development through milestone payments.

Intas Biopharmaceuticals has signed a Memorandum of Understanding (MoU) with Government of Gujarat in 2009 for setting up a separate manufacturing facility for MAbs, a recombinant mammalian platform product. The company will invest Rs 160 crore towards setting up a manufacturing facility at Sanand near Ahmedabad. The facility, fully-dedicated for mAbs, will undertake large-scale manufacturing of the recombinant product with a capacity of 5000L in phases. “As part of its Strategic Research Initiative (SRI), the company is focusing on cloning mAbs and developing proprietary and novel expression systems using different mammalian cell lines,” says Dr Mody.

These companies apart, Daftary group promoted Bharat Serums and Vaccines and Bangalore-based Avesthagen are some of the other notable companies that have chalked our serious plans for the space.

Challenges ahead
MAbs are complex protein molecules. In addition to the protein structure, often there is a carbohydrate moiety attached to the molecule. Characterization of such complex molecules is a challenge, this is why, very few companies in India are active in mAbs arena.  “Not only do you need sophisticated equipment to analyze mAbs, you also need skilled manpower to do this. Since most of these are immune-modulatory in nature, they have complex reactions with the human body.

Therefore, we have to determine the biological activity of these molecules using specific cell lines. Performing such bioassays is also a challenging,” adds Dr Iyer.

Industry experts agree that the mAbs market in India is in its nascent stage. In India, only few players are active in mAbs space. There are many players who have aspirations to enter the space as the next generation of biotech products would be mAbs. However, there are only a handful of companies that have products in the preclinical stage.

The reasons are many. “It is difficult to copy human mAbs, which is complex and expensive process. It takes a long time to develop and it needs some vigorous ground work and intensive research that Indian companies are yet to gain mastery,” adds Shetty.

In addition to this, the Drug Controller General of India (DCGI) is yet to come out with a set of systematic guidelines dedicated especially for mAbs. Companies like Dr Reddy’s Labs and Biocon have been the only two companies successful in bringing in products while the remaining are still in the development stage.”Shetty says, “It will take some time for India to become a lucrative market for mAbs. In biogenerics, too, the market would take time to pick up.  In addition to this, the high costs of investments involved can also be a barrier.

“MAbs business involves patents and for navigating through these patents requires exceptional skills,” adds Dr Mody.

Future prospects
By 2015 , due to the expected launch of many new therapies such as Denosumab and Teplizumab, the sales of mAbs is expected to reach Rs 3 lakh crore ($67.6 bn), with a CAGR of 13.8 percent between 2008 and 2015. The biotherapeutic market would be dominated with mAbs in next five years as most of the blockbuster molecules are going off-patented.

All the pharma majors have mAbs projects in their R&D portfolio. Introduction of newer monoclonal antibodies will greatly expand the market. Globally, the FDA had approved four new mAbs and EMA had approved seven new mAbs in 2009. There were at least six new mAbs under regulatory review, 26 mAbs (32 in 2008) are in phase III and over 100 are in phase II clinical trials. There are more than 150 mAbs molecule awaiting regulatory approval. In addition to this, several promising candidates  from companies like Pfizer are in phase III clinical trials.

In the recent past, Sanofi-aventis Chris Viehbacher, CEO of Sanofi-aventis, had commented that they had missed the ‘boat to biologics’ and are in active pursuit of this promising mAbs market. Sanofi-Aventis is converting a factory near Paris into a biotechnology development hub, with its doors wide open to smaller biotech companies looking to partner on projects. The French pharma giant says that the Rs 1,178 crore ($265 mn) venture marks their commitment to ramping up their work on biologics.  It is an opportunity for the company to do partnerships with biotechnology and research companies. The investment of nearly Rs 1,183 crore (€200 mn) will give rise to the first cell culture biotechnology platform of the group to produce mAbs from 2012.

On the other hand,  within the same time period, experts are cynical as to whether India can match up to global standards given a the huge  amount of investments and the complexity that the process involves. “I do not see that Indian companies achieving much by 2015 and taking their products globally is but a distant dream,” concludes an analyst.

Compared to India, China is a big market for mAbs. Some notable  companies include Union Stem Cell and Gene Engineering and Biotech pharmaceutical. In a serious effort towards innovation,China is moving towards areas like stem cells, mAbs, cancer and HIV development and vaccines with investments being pumped in both by the Government and foreign sources. India, experts opine needs exactly the same kind of backing if it need to bolster growth rates of the sector in the region.

monoclonal antibodies (mAb or moAb) are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell, in contrast to polyclonal antibodies which are made from several different immune cells. Monoclonal antibodies have monovalent affinity, in that they bind to the same epitope.

Given almost any substance, it is possible to produce monoclonal antibodies that specifically bind to that substance; they can then serve to detect or purify that substance. This has become an important tool in biochemistry, molecular biology and medicine. When used as medications, the non-proprietary drug name ends in -mab (see “Nomenclature of monoclonal antibodies“).

Discovery

The idea of a “magic bullet” was first proposed by Paul Ehrlich, who, at the beginning of the 20th century, postulated that, if a compound could be made that selectively targeted against a disease-causing organism, then a toxin for that organism could be delivered along with the agent of selectivity. He and Élie Metchnikoff received the 1908 Nobel Prize for Physiology or Medicine for this work, which led to an effective syphilis treatment by 1910.

In the 1970s, the B-cell cancer multiple myeloma was known, and it was understood that these cancerous B-cells all produce a single type of antibody (a paraprotein). This was used to study the structure of antibodies, but it was not yet possible to produce identical antibodies specific to a given antigen.

Production of monoclonal antibodies involving human–mouse hybrid cells was described by Jerrold Schwaber in 1973^[1] and remains widely cited among those using human-derived hybridomas,^[2] but claims of priority have been controversial. A science history paper on the subject gave some credit to Schwaber for inventing a technique that was widely cited, but stopped short of suggesting that he had been cheated.^[3] The invention was reduced to practice by Cotton and Milstein, and then by Kohler and Milstein. Georges Köhler, César Milstein, and Niels Kaj Jerne in 1975;^[4] who shared the Nobel Prize in Physiology or Medicine in 1984 for the discovery. The key idea was to use a line of myeloma cells that had lost their ability to secrete antibodies, come up with a technique to fuse these cells with healthy antibody-producing B-cells, and be able to select for the successfully fused cells. This was put into practice by Milstein and Köhler in their search for a laboratory tool to investigate antibody diversity.^[5]

In 1988, Greg Winter and his team pioneered the techniques to humanize monoclonal antibodies,^[6] removing the reactions that many monoclonal antibodies caused in some patients.

Production

Hybridoma cell production

Monoclonal antibodies are typically made by fusing myeloma cells with the spleen cells from a mouse that has been immunized with the desired antigen. However, recent advances have allowed the use of rabbit B-cells to form a rabbit hybridoma. Polyethylene glycol is used to fuse adjacent plasma membranes, but the success rate is low so a selective medium in which only fused cells can grow is used. This is possible because myeloma cells have lost the ability to synthesize hypoxanthine-guanine-phosphoribosyl transferase (HGPRT), an enzyme necessary for the salvage synthesis of nucleic acids. The absence of HGPRT is not a problem for these cells unless the de novo purine synthesis pathway is also disrupted. By exposing cells to aminopterin (a folic acid analogue, which inhibits dihydrofolate reductase, DHFR), they are unable to use the de novo pathway and become fully auxotrophic for nucleic acids requiring supplementation to survive.

The selective culture medium is called HAT medium because it contains hypoxanthine, aminopterin, and thymidine. This medium is selective for fused (hybridoma) cells. Unfused myeloma cells cannot grow because they lack HGPRT, and thus cannot replicate their DNA. Unfused spleen cells cannot grow indefinitely because of their limited life span. Only fused hybrid cells, referred to as hybridomas, are able to grow indefinitely in the media because the spleen cell partner supplies HGPRT and the myeloma partner has traits that make it immortal (similar to a cancer cell).

This mixture of cells is then diluted and clones are grown from single parent cells on microtitre wells. The antibodies secreted by the different clones are then assayed for their ability to bind to the antigen (with a test such as ELISA or Antigen Microarray Assay) or immuno-dot blot. The most productive and stable clone is then selected for future use.

The hybridomas can be grown indefinitely in a suitable cell culture medium. They can also be injected into mice (in the peritoneal cavity, surrounding the gut). There, they produce tumors secreting an antibody-rich fluid called ascites fluid.

The medium must be enriched during in-vitro selection to further favour hybridoma growth. This can be achieved by the use of a layer of feeder fibrocyte cells or supplement medium such as briclone. Culture-medium conditioned by macrophages can also be used. Production in cell culture is usually preferred as the ascites technique is painful to the animal. Where alternate techniques exist, this method (ascites) is considered unethical.

Purification of monoclonal antibodies

After obtaining either a media sample of cultured hybridomas or a sample of ascites fluid, the desired antibodies must be extracted. The contaminants in the cell culture sample would consist primarily of media components such as growth factors, hormones, and transferrins. In contrast, the in vivo sample is likely to have host antibodies, proteases, nucleases, nucleic acids, and viruses. In both cases, other secretions by the hybridomas such as cytokines may be present. There may also be bacterial contamination and, as a result, endotoxins that are secreted by the bacteria. Depending on the complexity of the media required in cell culture, and thus the contaminants in question, one method (in vivo or in vitro) may be preferable to the other.

The sample is first conditioned, or prepared for purification. Cells, cell debris, lipids, and clotted material are first removed, typically by centrifugation followed by filtration with a 0.45 µm filter. These large particles can cause a phenomenon called membrane fouling in later purification steps. In addition, the concentration of product in the sample may not be sufficient, especially in cases where the desired antibody is one produced by a low-secreting cell line. The sample is therefore condensed by ultrafiltration or dialysis.

Most of the charged impurities are usually anions such as nucleic acids and endotoxins. These are often separated by ion exchange chromatography.^[7] Either cation exchange chromatography is used at a low enough pH that the desired antibody binds to the column while anions flow through, or anion exchange chromatography is used at a high enough pH that the desired antibody flows through the column while anions bind to it. Various proteins can also be separated out along with the anions based on their isoelectric point (pI). For example, albumin has a pI of 4.8, which is significantly lower than that of most monoclonal antibodies, which have a pI of 6.1. In other words, at a given pH, the average charge of albumin molecules is likely to be more negative. Transferrin, on the other hand, has a pI of 5.9, so it cannot easily be separated out by this method. A difference in pI of at least 1 is necessary for a good separation.

Transferrin can instead be removed by size exclusion chromatography. The advantage of this purification method is that it is one of the more reliable chromatography techniques. Since we are dealing with proteins, properties such as charge and affinity are not consistent and vary with pH as molecules are protonated and deprotonated, while size stays relatively constant. Nonetheless, it has drawbacks such as low resolution, low capacity and low elution times.

A much quicker, single-step method of separation is Protein A/G affinity chromatography. The antibody selectively binds to Protein A/G, so a high level of purity (generally >80%) is obtained. However, this method may be problematic for antibodies that are easily damaged, as harsh conditions are generally used. A low pH can break the bonds to remove the antibody from the column. In addition to possibly affecting the product, low pH can cause Protein A/G itself to leak off the column and appear in the eluted sample. Gentle elution buffer systems that employ high salt concentrations are also available to avoid exposing sensitive antibodies to low pH. Cost is also an important consideration with this method because immobilized Protein A/G is a more expensive resin.

To achieve maximum purity in a single step, affinity purification can be performed, using the antigen to provide exquisite specificity for the antibody. In this method, the antigen used to generate the antibody is covalently attached to an agarose support. If the antigen is a peptide, it is commonly synthesized with a terminal cysteine, which allows selective attachment to a carrier protein, such as KLH during development and to the support for purification. The antibody-containing media is then incubated with the immobilized antigen, either in batch or as the antibody is passed through a column, where it selectively binds and can be retained while impurities are washed away. An elution with a low pH buffer or a more gentle, high salt elution buffer is then used to recover purified antibody from the support.

To further select for antibodies, the antibodies can be precipitated out using sodium sulfate or ammonium sulfate. Antibodies precipitate at low concentrations of the salt, while most other proteins precipitate at higher concentrations. The appropriate level of salt is added in order to achieve the best separation. Excess salt must then be removed by a desalting method such as dialysis.

The final purity can be analyzed using a chromatogram. Any impurities will produce peaks, and the volume under the peak indicates the amount of the impurity. Alternatively, gel electrophoresis and capillary electrophoresis can be carried out. Impurities will produce bands of varying intensity, depending on how much of the impurity is present.

Antibody heterogeneity

Product heterogeneity is common to monoclonal antibody and other recombinant biological production and is typically introduced either upstream during expression or downstream during manufacturing.

These variants are typically aggregates, deamidation products, glycosylation variants, oxidized amino acid side chains, as well as amino and carboxyl terminal amino acid additions.^[8] These seemingly minute changes in a monoclonal antibody’s structure can have a profound effect on preclinical stability and process optimization as well as therapeutic product potency, bioavailability, and immunogenicity. The generally accepted method of purification of process streams for monoclonal antibodies includes capture of the product target with Protein A, elution, acidification to inactivate potential Mammalian viruses, followed by cation exchange chromatography, and finally anion exchange chromatography.

Displacement chromatography has been used to identify and characterize these often unseen variants in quantities that are suitable for subsequent preclinical evaluation regimens such as animal pharmacokinetic studies.^[9][10] Knowledge gained during the preclinical development phase is critical for enhanced understanding of product quality and provides a basis for risk management and increased regulatory flexibility. The recent Food and Drug Administration’s Quality by Design initiative attempts to provide guidance on development and to facilitate design of products and processes that maximizes efficacy and safety profile while enhancing product manufacturability.^[11]

Recombinant

The production of recombinant monoclonal antibodies involves technologies, referred to as repertoire cloning or phage display/yeast display. Recombinant antibody engineering involves the use of viruses or yeast to create antibodies, rather than mice. These techniques rely on rapid cloning of immunoglobulin gene segments to create libraries of antibodies with slightly different amino acid sequences from which antibodies with desired specificities can be selected.^[12] The phage antibody libraries are a variant of the phage antigen libraries first invented by George Pieczenik^[13] These techniques can be used to enhance the specificity with which antibodies recognize antigens, their stability in various environmental conditions, their therapeutic efficacy, and their detectability in diagnostic applications.^[14] Fermentation chambers have been used to produce these antibodies on a large scale.

Chimeric antibodies

Early on, a major problem for the therapeutic use of monoclonal antibodies in medicine was that initial methods used to produce them yielded mouse, not human antibodies. While structurally similar, differences between the two were sufficient to invoke an immune response when murine monoclonal antibodies were injected into humans, resulting in their rapid removal from the blood, as well as systemic inflammatory effects, and the production of human anti-mouse antibodies (HAMA).^{[citation needed]}

In an effort to overcome this obstacle, approaches using recombinant DNA have been explored since the late 1980s. In one approach, mouse DNA encoding the binding portion of a monoclonal antibody was merged with human antibody-producing DNA in living cells. The expression of this chimeric DNA through cell culture yielded partially mouse, partially human monoclonal antibodies. For this product, the descriptive terms “chimeric” and “humanised” monoclonal antibody have been used to reflect the combination of mouse and human DNA sources used in the recombinant process.^[15]

‘Fully’ human monoclonal antibodies

Ever since the discovery that monoclonal antibodies could be generated, scientists have targeted the creation of ‘fully’ human antibodies to avoid some of the side effects of humanised or chimeric antibodies. Two successful approaches have been identified: transgenic mice^[16] and phage display.

Transgenic mice technology is by far the most successful approach to making ‘fully’ human monoclonal antibody therapeutics: 7 of the 9 ‘fully’ human monoclonal antibody therapeutics on the market were derived in this manner.^[17]

Transgenic mice have been exploited by a number of commercial organisations:

• Medarex — who marketed their UltiMab platform. Medarex were acquired in July 2009 by Bristol Myers Squibb^[18]
• Abgenix — who marketed their Xenomouse technology. Abgenix were acquired in April 2006 by Amgen.^[19]
• Regeneron‘s VelocImmune technology.^[20]
• Kymab – who market their Kymouse technology.^[21]

One of the most successful commercial organisations using phage display technology was Cambridge Antibody Technology (CAT). Scientists at CAT demonstrated that phage display could be used such that variable antibody domains could be expressed on filamentous phage antibodies. This was reported in a key Nature publication.^[22]

Other significant publications include:

• Marks JD, Hoogenboom HR, Bonnert TP, McCafferty J, Griffiths AD, Winter G (December 1991). “By-passing immunization. Human antibodies from V-gene libraries displayed on phage”. J. Mol. Biol. 222 (3): 581–597. doi:10.1016/0022-2836(91)90498-U. PMID 1748994.
• Carmen S, Jermutus L (July 2002). “Concepts in antibody phage display”. Brief Funct Genomic Proteomic 1 (2): 189–203. doi:10.1093/bfgp/1.2.189. PMID 15239904.

CAT developed their display technologies further into several, patented antibody discovery/functional genomics tools, which were named Proximol^TM[23] and ProAb^TM. ProAb was announced in December 1997^[24] and involved high throughput screening of antibody libraries against diseased and non-diseased tissue, whilst Proximol used a free radical enzymatic reaction to label molecules in proximity to a given protein.^[25][26]

Monoclonal antibodies have been generated and approved to treat cancer, cardiovascular disease, inflammatory diseases, macular degeneration, transplant rejection, multiple sclerosis, and viral infection (see monoclonal antibody therapy).

In August 2006 the Pharmaceutical Research and Manufacturers of America reported that U.S. companies had 160 different monoclonal antibodies in clinical trials or awaiting approval by the Food and Drug Administration.^[27]

Applications

Diagnostic tests

Once monoclonal antibodies for a given substance have been produced, they can be used to detect the presence of this substance. The Western blot test and immuno dot blot tests detect the protein on a membrane. They are also very useful in immunohistochemistry, which detect antigen in fixed tissue sections and immunofluorescence test, which detect the substance in a frozen tissue section or in live cells.

Therapeutic treatment

Cancer treatment

One possible treatment for cancer involves monoclonal antibodies that bind only to cancer cell-specific antigens and induce an immunological response against the target cancer cell. Such mAb could also be modified for delivery of a toxin, radioisotope, cytokine or other active conjugate; it is also possible to design bispecific antibodies that can bind with their Fab regions both to target antigen and to a conjugate or effector cell. In fact, every intact antibody can bind to cell receptors or other proteins with its Fc region.

The illustration below shows all these possibilities:

MAbs approved by the FDA include^[29]

• Bevacizumab
• Cetuximab
• Panitumumab
• Trastuzumab

Autoimmune diseases

Monoclonal antibodies used for autoimmune diseases include infliximab and adalimumab, which are effective in rheumatoid arthritis, Crohn’s disease and ulcerative Colitis by their ability to bind to and inhibit TNF-α.^[30] Basiliximab and daclizumab inhibit IL-2 on activated T cells and thereby help prevent acute rejection of kidney transplants.^[30] Omalizumab inhibits human immunoglobulin E (IgE) and is useful in moderate-to-severe allergic asthma.

Examples

Below are examples of clinically important monoclonal antibodies.

Main category	Type	Application	Mechanism/Target	Mode
Anti- inflammatory	infliximab[30]	rheumatoid arthritis Crohn’s disease Ulcerative Colitis	inhibits TNF-α	chimeric
	adalimumab	rheumatoid arthritis Crohn’s disease Ulcerative Colitis	inhibits TNF-α	human
	basiliximab[30]	Acute rejection of kidney transplants	inhibits IL-2 on activated T cells	chimeric
	daclizumab[30]	Acute rejection of kidney transplants	inhibits IL-2 on activated T cells	humanized
	omalizumab	moderate-to-severe allergic asthma	inhibits human immunoglobulin E (IgE)	humanized
Anti-cancer	gemtuzumab[30]	relapsed acute myeloid leukemia	targets myeloid cell surface antigen CD33 on leukemia cells	humanized
	alemtuzumab[30]	B cell leukemia	targets an antigen CD52 on T- and B-lymphocytes	humanized
	rituximab[30]	non-Hodgkin’s lymphoma	targets phosphoprotein CD20 on B lymphocytes	chimeric
	trastuzumab	breast cancer with HER2/neu overexpression	targets the HER2/neu (erbB2) receptor	humanized
	nimotuzumab	Approved in squamous cell carcinomas, Glioma Clinical trials for other indications underway	EGFR inhibitor	Humanized
	cetuximab	Approved in squamous cell carcinomas, colorectal carcinoma	EGFR inhibitor	Chimeric
	bevacizumab	Anti-angiogenic cancer therapy	inhibits VEGF	humanized
Other	palivizumab[30]	RSV infections in children	inhibits an RSV fusion (F) protein	humanized
	abciximab[30]	Prevent coagulation in coronary angioplasty	inhibits the receptor GpIIb/IIIa on platelets	chimeric

See also

• Antibody mimetic
• Immunotoxins, which sometimes use monoclonal antibodies as the targeting mechanism
• List of monoclonal antibodies
• Monoclonal antibody therapy
• Nomenclature of monoclonal antibodies
• Polyclonal antibodies
• Queen Mab Small mythological figure symbolizing hope (popular culture, used as biotech pun).

References

reference 24: should be

chapter 34. Therapeutic Antibodies and Immunologic Conjugates. In Clinical Oncology, 4th Edition, edited by Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB and McKenna G. Publisher Elsevier Inc. 2008.

External links

Library resources
About Monoclonal antibody
Resources in your library Resources in other libraries

• Monoclonal Antibodies Animation (Flash Required)
• Monoclonal Antibodies, from John W. Kimball’s online biology textbook
• Monoclonal antibodies at the US National Library of Medicine Medical Subject Headings (MeSH)
• Antibodypedia, open-access virtual repository publishing data and commentary on any antibodies available to the scientific community.

list of monoclonal antibodies

http://en.wikipedia.org/wiki/List_of_monoclonal_antibodies

This list includes approved and investigational drugs as well as drugs that have been withdrawn from market; consequently, the column Use does not necessarily indicate clinical usage.

Name	Trade name	Type	Source	Target	Use
3F8		mab	mouse	GD2	neuroblastoma
8H9[1]		mab	mouse	B7-H3	neuroblastoma, sarcoma, metastatic brain cancers
Abagovomab[2]		mab	mouse	CA-125 (imitation)	ovarian cancer
Abciximab	ReoPro	Fab	chimeric	CD41 (integrin alpha-IIb)	platelet aggregation inhibitor
Actoxumab[3]		mab	human	Clostridium difficile	Clostridium difficile infection
Adalimumab	Humira	mab	human	TNF-α	Rheumatoid arthritis, Crohn’s Disease, Plaque Psoriasis, Psoriatic Arthritis, Ankylosing Spondylitis, Juvenile Idiopathic Arthritis
Adecatumumab[4]		mab	human	EpCAM	prostate and breast cancer
Afelimomab		F(ab’)2	mouse	TNF-α	sepsis
Afutuzumab[5]		mab	humanized	CD20	lymphoma
Alacizumab pegol[6]		F(ab’)2	humanized	VEGFR2	cancer
ALD518[7]		?	humanized	IL-6	rheumatoid arthritis
Alemtuzumab[8]	Campath, MabCampath	mab	humanized	CD52	CLL, CTCL
Alirocumab[9]		mab	human	NARP-1	hypercholesterolemia
Altumomab pentetate	Hybri-ceaker	mab	mouse	CEA	colorectal cancer (diagnosis)
Amatuximab[10]		mab	chimeric	mesothelin	cancer
Anatumomab mafenatox		Fab	mouse	TAG-72	non-small cell lung carcinoma
Anifrolumab[11]		mab	human	interferon α/β receptor	systemic lupus erythematosus
Anrukinzumab[6] (= IMA-638)[12]		mab	humanized	IL-13	?
Apolizumab[13]		mab	humanized	HLA-DR ?	hematological cancers
Arcitumomab	CEA-Scan	Fab’	mouse	CEA	gastrointestinal cancers (diagnosis)
Aselizumab[14]		mab	humanized	L-selectin (CD62L)	severely injured patients
Atinumab[15]		mab	human	RTN4	?
Atlizumab (= tocilizumab)	Actemra, RoActemra	mab	humanized	IL-6 receptor	rheumatoid arthritis
Atorolimumab		mab	human	Rhesus factor	hemolytic disease of the newborn[citation needed]
Bapineuzumab[16]		mab	humanized	beta amyloid	Alzheimer’s disease
Basiliximab	Simulect	mab	chimeric	CD25 (α chain of IL-2 receptor)	prevention of organ transplant rejections
Bavituximab[2]		mab	chimeric	phosphatidylserine	cancer, viral infections
Bectumomab	LymphoScan	Fab’	mouse	CD22	non-Hodgkin’s lymphoma (detection)
Belimumab	Benlysta, LymphoStat-B	mab	human	BAFF	non-Hodgkin lymphoma etc.
Benralizumab		mab	humanized	CD125	asthma
Bertilimumab[14]		mab	human	CCL11 (eotaxin-1)	severe allergic disorders
Besilesomab[17]	Scintimun	mab	mouse	CEA-related antigen	inflammatory lesions and metastases (detection)
Bevacizumab[8]	Avastin	mab	humanized	VEGF-A	metastatic cancer
Bezlotoxumab[18]		mab	human	Clostridium difficile	Clostridium difficile infection
Biciromab	FibriScint	Fab’	mouse	fibrin II, beta chain	thromboembolism (diagnosis)
Bimagrumab[19]		mab	human	ACVR2B	myostatin inhibitor
Bivatuzumab mertansine		mab	humanized	CD44 v6	squamous cell carcinoma
Blinatumomab		BiTE	mouse	CD19	cancer
Blosozumab[20]		mab	humanized	SOST	osteoporosis
Brentuximab vedotin[21]		mab	chimeric	CD30 (TNFRSF8)	hematologic cancers
Briakinumab[22]		mab	human	IL-12, IL-23	psoriasis, rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis
Brodalumab[23]		mab	human	IL-17	inflammatory diseases
Canakinumab[24]	Ilaris	mab	human	IL-1?	rheumatoid arthritis
Cantuzumab mertansine		mab	humanized	mucin CanAg	colorectal cancer etc.
Cantuzumab ravtansine[20]		mab	humanized	MUC1	cancers
Caplacizumab[25]		mab	humanized	VWF	?
Capromab pendetide	Prostascint	mab	mouse	prostatic carcinoma cells	prostate cancer (detection)
Carlumab[26]		mab	human	MCP-1	oncology/immune indications
Catumaxomab[16]	Removab	3funct	rat/mouse hybrid	EpCAM, CD3	ovarian cancer, malignant ascites, gastric cancer
CC49		mab	mouse	TAG-72	tumor detection
Cedelizumab		mab	humanized	CD4	prevention of organ transplant rejections, treatment of autoimmune diseases
Certolizumab pegol[4]	Cimzia	Fab’	humanized	TNF-α	Crohn’s disease
Cetuximab	Erbitux	mab	chimeric	EGFR	metastatic colorectal cancer and head and neck cancer
Ch.14.18 [1]		mab	chimeric	???	neuroblastoma
Citatuzumab bogatox[5]		Fab	humanized	EpCAM	ovarian cancer and other solid tumors
Cixutumumab		mab	human	IGF-1 receptor	solid tumors
Clazakizumab[27]		mab	humanized	Oryctolagus cuniculus	rheumatoid arthritis
Clenoliximab		mab	chimeric	CD4	rheumatoid arthritis
Clivatuzumab tetraxetan[28]	hPAM4-Cide	mab	humanized	MUC1	pancreatic cancer
Conatumumab[5]		mab	human	TRAIL-R2	cancer
Concizumab[19]		mab	humanized	TFPI	bleeding
Crenezumab[29]		mab	humanized	1-40-β-amyloid	Alzheimer’s disease
CR6261		mab	human	Influenza A hemagglutinin	infectious disease/influenza A
Dacetuzumab[6]		mab	humanized	CD40	hematologic cancers
Daclizumab	Zenapax	mab	humanized	CD25 (α chain of IL-2 receptor)	prevention of organ transplant rejections
Dalotuzumab[30]		mab	humanized	insulin-like growth factor I receptor	cancer etc.
Daratumumab[31]		mab	human	CD38 (cyclic ADP ribose hydrolase)	?
Demcizumab[32]		mab	humanized	DLL4	cancer
Denosumab[33]	Prolia	mab	human	RANKL	osteoporosis, bone metastases etc.
Detumomab		mab	mouse	B-lymphoma cell	lymphoma
Dorlimomab aritox[34]		F(ab’)2	mouse	?	?
Drozitumab[35]		mab	human	DR5	cancer etc.
Duligotumab[36]		mab	human	HER3	?
Dupilumab[37]		mab	human	IL4	atopic diseases
Dusigitumab[38]		mab	human	ILGF2	cancer
Ecromeximab[13]		mab	chimeric	GD3 ganglioside	malignant melanoma
Eculizumab[13]	Soliris	mab	humanized	C5	paroxysmal nocturnal hemoglobinuria
Edobacomab		mab	mouse	endotoxin	sepsis caused by Gram-negative bacteria
Edrecolomab	Panorex	mab	mouse	EpCAM	colorectal carcinoma
Efalizumab[39]	Raptiva	mab	humanized	LFA-1 (CD11a)	psoriasis (blocks T-cell migration)
Efungumab[2]	Mycograb	scFv	human	Hsp90	invasive Candida infection
Eldelumab[40]		mab	human	interferon gamma-induced protein	Crohn’s disease, ulcerative colitis
Elotuzumab		mab	humanized	SLAMF7	multiple myeloma
Elsilimomab		mab	mouse	IL-6	?
Enavatuzumab[41]		mab	humanized	TWEAK receptor	cancer etc.
Enlimomab pegol[42]		mab	mouse	ICAM-1 (CD54)	?
Enokizumab[43]		mab	humanized	IL9	asthma
Enoticumab[36]		mab	human	DLL4	?
Ensituximab[44]		mab	chimeric	5AC	cancer
Epitumomab cituxetan[45]		mab	mouse	episialin	?
Epratuzumab		mab	humanized	CD22	cancer, SLE
Erlizumab[46]		F(ab’)2	humanized	ITGB2 (CD18)	heart attack, stroke, traumatic shock
Ertumaxomab[16]	Rexomun	3funct	rat/mouse hybrid	HER2/neu, CD3	breast cancer etc.
Etaracizumab	Abegrin	mab	humanized	integrin αvβ3	melanoma, prostate cancer, ovarian cancer etc.
Etrolizumab[47]		mab	humanized	integrin α7 β7	inflammatory bowel disease
Evolocumab[19]		mab	human	PCSK9	hypocholesterolemia
Exbivirumab[48]		mab	human	hepatitis B surface antigen	hepatitis B
Fanolesomab[49]	NeutroSpec	mab	mouse	CD15	appendicitis (diagnosis)
Faralimomab		mab	mouse	interferon receptor	?
Farletuzumab		mab	humanized	folate receptor 1	ovarian cancer
Fasinumab[50]		mab	human	HNGF	?
FBTA05[51][52]	Lymphomun	3funct	rat/mouse hybrid	CD20	chronic lymphocytic leukaemia
Felvizumab		mab	humanized	respiratory syncytial virus	respiratory syncytial virus infection
Fezakinumab[53][54][55]		mab	human	IL-22	rheumatoid arthritis, psoriasis
Ficlatuzumab[56]		mab	humanized	HGF	cancer etc.
Figitumumab		mab	human	IGF-1 receptor	adrenocortical carcinoma, non-small cell lung carcinoma etc.
Flanvotumab[57]		mab	human	glycoprotein 75	melanoma
Fontolizumab[13]	HuZAF	mab	humanized	IFN-γ	Crohn’s disease etc.
Foralumab[58]		mab	human	CD3 epsilon	?
Foravirumab[5]		mab	human	rabies virus glycoprotein	rabies (prophylaxis)
Fresolimumab[59]		mab	human	TGF-β	idiopathic pulmonary fibrosis, focal segmental glomerulosclerosis, cancer
Fulranumab[60]		mab	human	NGF	pain
Futuximab[36]		mab	chimeric	EGFR	?
Galiximab		mab	chimeric	CD80	B-cell lymphoma
Ganitumab[61]		mab	human	IGF-I	cancer
Gantenerumab[24]		mab	human	beta amyloid	Alzheimer’s disease
Gavilimomab[46]		mab	mouse	CD147 (basigin)	graft versus host disease
Gemtuzumab ozogamicin	Mylotarg	mab	humanized	CD33	acute myelogenous leukemia
Gevokizumab[62]		mab	humanized	IL-1β	diabetes etc.
Girentuximab[31]	Rencarex	mab	chimeric	carbonic anhydrase 9 (CA-IX)	clear cell renal cell carcinoma[63]
Glembatumumab vedotin[64][65]		mab	human	GPNMB	melanoma, breast cancer
Golimumab[48]	Simponi	mab	human	TNF-α	rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis
Gomiliximab		mab	chimeric	CD23 (IgE receptor)	allergic asthma
GS6624 [66]		mab	?	?	idiopathic pulmonary fibrosis and solid tumors
Guselkumab[67]		mab	human	IL13	psoriasis
Ibalizumab[24]		mab	humanized	CD4	HIV infection
Ibritumomab tiuxetan	Zevalin	mab	mouse	CD20	non-Hodgkin’s lymphoma
Icrucumab[68]		mab	human	VEGFR-1	cancer etc.
Igovomab	Indimacis-125	F(ab’)2	mouse	CA-125	ovarian cancer (diagnosis)
Imciromab	Myoscint	mab	mouse	cardiac myosin	cardiac imaging
Imgatuzumab[36]		mab	humanized	EGFR	cancer
Inclacumab[25]		mab	human	selectin P	?
Indatuximab ravtansine[20]		mab	chimeric	SDC1	cancer
Infliximab	Remicade	mab	chimeric	TNF-α	rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn’s disease, ulcerative colitis
Intetumumab[69][70][71]		mab	human	CD51	solid tumors (prostate cancer, melanoma)
Inolimomab		mab	mouse	CD25 (α chain of IL-2 receptor)	graft versus host disease
Inotuzumab ozogamicin[17]		mab	humanized	CD22	cancer
Ipilimumab[33]	Yervoy	mab	human	CD152	melanoma
Iratumumab[33]		mab	human	CD30 (TNFRSF8)	Hodgkin’s lymphoma
Itolizumab[58]		mab	humanized	CD6	?
Ixekizumab[72]		mab	humanized	IL-17A	autoimmune diseases
Keliximab		mab	chimeric	CD4	chronic asthma
Labetuzumab[39]	CEA-Cide	mab	humanized	CEA	colorectal cancer
Lambrolizumab[73]		mab	humanized	PDCD1	antineoplastic agent
Lampalizumab[36]		mab	humanized	CFD	?
Lebrikizumab[74]		mab	humanized	IL-13	asthma
Lemalesomab[46]		mab	mouse	NCA-90 (granulocyte antigen)	diagnostic agent
Lerdelimumab[8]		mab	human	TGF beta 2	reduction of scarring after glaucoma surgery
Lexatumumab[2]		mab	human	TRAIL-R2	cancer
Libivirumab[48]		mab	human	hepatitis B surface antigen	hepatitis B
Ligelizumab[36]		mab	humanized	IGHE	?
Lintuzumab		mab	humanized	CD33	cancer
Lirilumab[36]		mab	human	KIR2D	?
Lodelcizumab[19]		mab	humanized	PCSK9	hypercholesterolemia
Lorvotuzumab mertansine		mab	humanized	CD56	cancer
Lucatumumab[6]		mab	human	CD40	multiple myeloma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma
Lumiliximab[4]		mab	chimeric	CD23 (IgE receptor)	chronic lymphocytic leukemia
Mapatumumab[16]		mab	human	TRAIL-R1	cancer
Margetuximab[75]		mab	humanized	ch4D5	cancer
Maslimomab		?	mouse	T-cell receptor	?
Mavrilimumab[76]		mab	human	GMCSF receptor α-chain	rheumatoid arthritis
Matuzumab[14]		mab	humanized	EGFR	colorectal, lung and stomach cancer
Mepolizumab	Bosatria	mab	humanized	IL-5	asthma and white blood cell diseases
Metelimumab[49]		mab	human	TGF beta 1	systemic scleroderma
Milatuzumab[6]		mab	humanized	CD74	multiple myeloma and other hematological malignancies
Minretumomab		mab	mouse	TAG-72	?
Mitumomab		mab	mouse	GD3 ganglioside	small cell lung carcinoma
Mogamulizumab[77]		mab	humanized	CCR4	cancer
Morolimumab		mab	human	Rhesus factor	?
Motavizumab[2]	Numax	mab	humanized	respiratory syncytial virus	respiratory syncytial virus (prevention)
Moxetumomab pasudotox[78]		mab	mouse	CD22	cancer
Muromonab-CD3	Orthoclone OKT3	mab	mouse	CD3	prevention of organ transplant rejections
Nacolomab tafenatox		Fab	mouse	C242 antigen	colorectal cancer
Namilumab[15]		mab	human	CSF2	?
Naptumomab estafenatox[79]		Fab	mouse	5T4	non-small cell lung carcinoma, renal cell carcinoma
Narnatumab[80]		mab	human	RON	cancer
Natalizumab	Tysabri	mab	humanized	integrin α4	multiple sclerosis, Crohn’s disease
Nebacumab		mab	human	endotoxin	sepsis
Necitumumab[81]		mab	human	EGFR	non-small cell lung carcinoma
Nerelimomab		mab	mouse	TNF-α	?
Nesvacumab[82]		mab	human	angiopoietin 2	cancer
Nimotuzumab[33][83]	Theracim, Theraloc	mab	humanized	EGFR	squamous cell carcinoma, head and neck cancer, nasopharyngeal cancer, glioma
Nivolumab[84]		mab	human	IgG4	cancer
Nofetumomab merpentan	Verluma	Fab	mouse	?	cancer (diagnosis)
Ocaratuzumab[85]		mab	humanized	CD20	cancer
Ocrelizumab[33]		mab	humanized	CD20	rheumatoid arthritis, lupus erythematosus etc.
Odulimomab		mab	mouse	LFA-1 (CD11a)	prevention of organ transplant rejections, immunological diseases
Ofatumumab[16]	Arzerra	mab	human	CD20	chronic lymphocytic leukemia etc.
Olaratumab		mab	human	PDGF-R α	cancer
Olokizumab[58]		mab	humanized	IL6	?
Omalizumab[46]	Xolair	mab	humanized	IgE Fc region	allergic asthma
Onartuzumab[86]		mab	humanized	human scatter factor receptor kinase	cancer
Ontuxizumab[87]		mab	chimeric/humanized	TEM1	cancer
Oportuzumab monatox[81]		scFv	humanized	EpCAM	cancer
Oregovomab[49]	OvaRex	mab	mouse	CA-125	ovarian cancer
Orticumab[36]		mab	human	oxLDL	?
Otelixizumab[6]		mab	chimeric/humanized	CD3	diabetes mellitus type 1
Oxelumab[88]		mab	human	OX-40	asthma
Ozanezumab[89]		mab	humanized	NOGO-A	ALS and multiple sclerosis
Ozoralizumab[90]		mab	humanized	TNF-α	inflammation
Pagibaximab[16]		mab	chimeric	lipoteichoic acid	sepsis (Staphylococcus)
Palivizumab	Synagis, Abbosynagis	mab	humanized	F protein of respiratory syncytial virus	respiratory syncytial virus (prevention)
Panitumumab[48]	Vectibix	mab	human	EGFR	colorectal cancer
Panobacumab[81]		mab	human	Pseudomonas aeruginosa	Pseudomonas aeruginosa infection
Parsatuzumab[36]		mab	human	EGFL7	cancer
Pascolizumab[13]		mab	humanized	IL-4	asthma
Pateclizumab[20]		mab	humanized	LTA	TNF
Patritumab[25]		mab	human	HER3	cancer
Pemtumomab	Theragyn	?	mouse	MUC1	cancer
Perakizumab[36]		mab	humanized	IL17A	arthritis
Pertuzumab	Omnitarg	mab	humanized	HER2/neu	cancer
Pexelizumab[39]		scFv	humanized	C5	reduction of side effects of cardiac surgery
Pidilizumab[91]		mab	humanized	PD-1	cancer and infectious diseases
Pinatuzumab vedotin[19]		mab	humanized	CD22	cancer
Pintumomab		mab	mouse	adenocarcinoma antigen	adenocarcinoma (imaging)
Placulumab[92]		mab	human	human TNF	?
Polatuzumab vedotin[19]		mab	humanized	CD79B	?
Ponezumab[93]		mab	humanized	human beta-amyloid	Alzheimer’s disease
Priliximab		mab	chimeric	CD4	Crohn’s disease, multiple sclerosis
Pritoxaximab[19]		mab	chimeric	E. coli shiga toxin type-1	?
Pritumumab		mab	human	vimentin	brain cancer
PRO 140		?	humanized	CCR5	HIV infection
Quilizumab[25]		mab	humanized	IGHE	?
Racotumomab[81]		mab	mouse	N–glycolylneuraminic acid	cancer
Radretumab[15]		mab	human	fibronectin extra domain-B	cancer
Rafivirumab[5]		mab	human	rabies virus glycoprotein	rabies (prophylaxis)
Ramucirumab		mab	human	VEGFR2	solid tumors
Ranibizumab[4]	Lucentis	Fab	humanized	VEGF-A	macular degeneration (wet form)
Raxibacumab[17]		mab	human	anthrax toxin, protective antigen	anthrax (prophylaxis and treatment)
Regavirumab		mab	human	cytomegalovirus glycoprotein B	cytomegalovirus infection
Reslizumab[39]		mab	humanized	IL-5	inflammations of the airways, skin and gastrointestinal tract
Rilotumumab[94]		mab	human	HGF	solid tumors
Rituximab	MabThera, Rituxan	mab	chimeric	CD20	lymphomas, leukemias, some autoimmune disorders
Robatumumab		mab	human	IGF-1 receptor	cancer
Roledumab[58]		mab	human	RHD	?
Romosozumab[95]		mab	humanized	scleroscin	osteoporosis
Rontalizumab[96]		mab	humanized	IFN-α	systemic lupus erythematosus
Rovelizumab	LeukArrest	mab	humanized	CD11, CD18	haemorrhagic shock etc.
Ruplizumab[8]	Antova	mab	humanized	CD154 (CD40L)	rheumatic diseases
Samalizumab[97]		mab	humanized	CD200	cancer
Sarilumab[98]		mab	human	IL6	rheumatoid arthritis, ankylosing spondylitis
Satumomab pendetide		mab	mouse	TAG-72	cancer (diagnosis)
Secukinumab[99]		mab	human	IL-17A	uveitis, rheumatoid arthritis psoriasis
Seribantumab[19]		mab	human	ERBB3	cancer
Setoxaximab[19]		mab	chimeric	E. coli shiga toxin type-1	?
Sevirumab		?	human	cytomegalovirus	cytomegalovirus infection
Sibrotuzumab		mab	humanized	FAP	cancer
Sifalimumab[100]		mab	humanized	IFN-α	SLE, dermatomyositis, polymyositis
Siltuximab		mab	chimeric	IL-6	cancer
Simtuzumab[36]		mab	humanized	LOXL2	?
Siplizumab[13]		mab	humanized	CD2	psoriasis, graft-versus-host disease (prevention)
Sirukumab[101]		mab	human	IL-6	rheumatoid arthritis
Solanezumab[81]		mab	humanized	beta amyloid	Alzheimer’s disease
Solitomab[25]		mab	mouse	EpCAM	?
Sonepcizumab[102]		?	humanized	sphingosine-1-phosphate	choroidal and retinal neovascularization
Sontuzumab[83]		mab	humanized	episialin	?
Stamulumab[33][83]		mab	human	myostatin	muscular dystrophy
Sulesomab	LeukoScan	Fab’	mouse	NCA-90 (granulocyte antigen)	osteomyelitis (imaging)
Suvizumab[64]		mab	humanized	HIV-1	viral infections
Tabalumab[103]		mab	human	BAFF	B-cell cancers
Tacatuzumab tetraxetan	AFP-Cide	mab	humanized	alpha-fetoprotein	cancer
Tadocizumab[83]		Fab	humanized	integrin αIIbβ3	percutaneous coronary intervention
Talizumab		mab	humanized	IgE	allergic reaction
Tanezumab[5]		mab	humanized	NGF	pain
Taplitumomab paptox[46]		mab	mouse	CD19	cancer[citation needed]
Tefibazumab[17]	Aurexis	mab	humanized	clumping factor A	Staphylococcus aureus infection
Telimomab aritox		Fab	mouse	?	?
Tenatumomab[6]		mab	mouse	tenascin C	cancer
Teneliximab[13]		mab	chimeric	CD40	?
Teplizumab[24]		mab	humanized	CD3	diabetes mellitus type 1
Teprotumumab[104]		mab	human	CD221	hematologic tumors
TGN1412		?	humanized	CD28	chronic lymphocytic leukemia, rheumatoid arthritis
Ticilimumab (= tremelimumab)		mab	human	CTLA-4	cancer
Tildrakizumab[105]		mab	humanized	IL23	immunologically mediated inflammatory disorders
Tigatuzumab[6]		mab	humanized	TRAIL-R2	cancer
TNX-650		?	humanized	IL-13	Hodgkin’s lymphoma
Tocilizumab[4] (= atlizumab)	Actemra, RoActemra	mab	humanized	IL-6 receptor	rheumatoid arthritis
Toralizumab[13]		mab	humanized	CD154 (CD40L)	rheumatoid arthritis, lupus nephritis etc.
Tositumomab	Bexxar	?	mouse	CD20	follicular lymphoma
Tovetumab[106]		mab	human	CD140a	cancer
Tralokinumab[107]		mab	human	IL-13	asthma etc.
Trastuzumab	Herceptin	mab	humanized	HER2/neu	breast cancer
TRBS07[108]	Ektomab	3funct	?	GD2	melanoma
Tregalizumab[15]		mab	humanized	CD4	?
Tremelimumab		mab	human	CTLA-4	cancer
Tucotuzumab celmoleukin[33][83]		mab	humanized	EpCAM	cancer
Tuvirumab		?	human	hepatitis B virus	chronic hepatitis B
Ublituximab[15]		mab	chimeric	MS4A1	cancer
Urelumab[109]		mab	human	4-1BB	cancer etc.
Urtoxazumab[4]		mab	humanized	Escherichia coli	diarrhoea caused by E. coli
Ustekinumab[5]	Stelara	mab	human	IL-12, IL-23	multiple sclerosis, psoriasis, psoriatic arthritis
Vantictumab[110]		mab	human	Frizzled receptor	cancer
Vapaliximab[13]		mab	chimeric	AOC3 (VAP-1)	?
Vatelizumab[20]		mab	humanized	ITGA2	?
Vedolizumab		mab	humanized	integrin α4β7	Crohn’s disease, ulcerative colitis
Veltuzumab[6]		mab	humanized	CD20	non-Hodgkin’s lymphoma
Vepalimomab		mab	mouse	AOC3 (VAP-1)	inflammation
Vesencumab[15]		mab	human	NRP1	?
Visilizumab[46]	Nuvion	mab	humanized	CD3	Crohn’s disease, ulcerative colitis
Volociximab[16]		mab	chimeric	integrin α5β1	solid tumors
Vorsetuzumab mafodotin[111]		mab	humanized	CD70	cancer
Votumumab	HumaSPECT	mab	human	tumor antigen CTAA16.88	colorectal tumors
Zalutumumab[16]	HuMax-EGFr	mab	human	EGFR	squamous cell carcinoma of the head and neck
Zanolimumab[4]	HuMax-CD4	mab	human	CD4	rheumatoid arthritis, psoriasis, T-cell lymphoma
Zatuximab[36]		mab	chimeric	HER1	cancer
Ziralimumab[46]		mab	human	CD147 (basigin)	?
Zolimomab aritox		mab	mouse	CD5	systemic lupus erythematosus, graft-versus-host disease