MONOCLONAL ANTIBODIES

Globally, the monoclonal antibodies market has emerged as a major money spinner for most companies. Indian companies are also tapping this potential market but the common issue faced by them is related to investment and process complexity

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.

Crystal Structure of Rituximab Fab in complex with an epitope peptide 2osl

Crystal Structure of Rituximab Fab in complex with an epitope peptide 2osl

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.

Different Types of Antibodies

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.

Figure #3

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

Researchers looking at slides of cultures of cells that make monoclonal antibodies. These are grown in a lab and the researchers are analyzing the products to select the most promising of them.

Monoclonal antibodies can be grown in unlimited quantities in the bottles shown in this picture.

Technician hand-filling wells with a liquid for a research test. This test involves preparation of cultures in which hybrids are grown in large quantities to produce desired antibody. This is effected by fusing myeloma cell and mouse lymphocyte to form a hybrid cell (hybridoma).

Lab technician bathing prepared slides in a solution. This technician prepares slides of monoclonal antibodies for researchers. The cells shown are labeling human breast cancer.

Hybridoma cell production

Further information: Hybridoma technology

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

Main article: 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:

CAT developed their display technologies further into several, patented antibody discovery/functional genomics tools, which were named ProximolTM[23] and ProAbTM. 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.

Monoclonal antibodies for cancer. ADEPT, antibody directed enzyme prodrug therapy; ADCC, antibody dependent cell-mediated cytotoxicity; CDC, complement dependent cytotoxicity; MAb, monoclonal antibody; scFv, single-chain Fv fragment.[28]

The illustration below shows all these possibilities:

MAbs approved by the FDA include[29]

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

For a more comprehensive list, see List of monoclonal antibodies.
For a list of FDA approved therapeutic antibodies, see Monoclonal antibody therapy.

Below are examples of clinically important monoclonal antibodies.

Main category Type Application Mechanism/Target Mode
Anti-
inflammatory
infliximab[30] inhibits TNF-α chimeric
adalimumab inhibits TNF-α human
basiliximab[30] inhibits IL-2 on activated T cells chimeric
daclizumab[30] inhibits IL-2 on activated T cells humanized
omalizumab
  • moderate-to-severe allergic asthma
inhibits human immunoglobulin E (IgE) humanized
Anti-cancer gemtuzumab[30] targets myeloid cell surface antigen CD33 on leukemia cells humanized
alemtuzumab[30] targets an antigen CD52 on T- and B-lymphocytes humanized
rituximab[30] targets phosphoprotein CD20 on B lymphocytes chimeric
trastuzumab
  • breast cancer with HER2/neu overexpression
targets the HER2/neu (erbB2) receptor humanized
nimotuzumab EGFR inhibitor Humanized
cetuximab EGFR inhibitor Chimeric
bevacizumab inhibits VEGF humanized
Other palivizumab[30]
  • RSV infections in children
inhibits an RSV fusion (F) protein humanized
abciximab[30] inhibits the receptor GpIIb/IIIa on platelets chimeric

See also

References

  1. Schwaber, J.; Cohen, E. P. (1973). “Human x mouse somatic cell hybrid clone secreting immunoglobulins of both parental types”. Nature 244 (5416): 444–447. Bibcode:1973Natur.244..444S. doi:10.1038/244444a0. PMID 4200460.  edit
  2. Jump up ^ Science Citation Index
  3. Jump up ^ Cambrosio, A.; Keating, P. (1992). “Between fact and technique: the beginnings of hybridoma technology”. Journal of the History of Biology 25 (2): 175–230. doi:10.1007/BF00162840. PMID 11623041edit
  4. Jump up ^ Köhler, G.; Milstein, C. (1975). “Continuous cultures of fused cells secreting antibody of predefined specificity”. Nature 256 (5517): 495–497. Bibcode:1975Natur.256..495K. doi:10.1038/256495a0. PMID 1172191edit
  5. Jump up ^ The Story of César Milstein and Monoclonal Antibodies.
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  27. Jump up ^ PhRMA Reports Identifies More than 400 Biotech Drugs in Development. Pharmaceutical Technology, August 24, 2006. Retrieved 2006-09-04.
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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

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 Nglycolylneuraminic 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

 

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