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Jin Zhang M.D., Ph.D is editor at The Pharmaceutical Consultant.
In the face of booming antibody market, China has jumped into the antibody-drug conjugate space. Jin Zhang reports.
In the recent years, antibody-drug conjugates (ADC) have been gradually gaining steam and become one of the rising stars in the oncology therapy field. Normally, they are consisted of three components – cytotoxic drugs, antibodies, and linkers – and can accurately deliver toxins to their site of action. Not surprisingly, because of their precision, this new form of cancer therapy is equipped with a number of benefits, including reduced toxin load, decreased off-target side reactions, and increased tumor killing effects.
What disease can be treated with an ADC is primarily determined by its antibody component. An ideal target should have a high-level expression of a specific antigen. Thus, antibodies can direct toxins to the right location to exert their killing effects. Thanks to their high accuracy, ADCs can significantly improve the survival of patients, especially compared to combination therapies of antibodies and chemo. In addition, it also has a large therapeutic window, thus giving new life to toxic drugs which were previously too poisonous for chemotherapy.
However, there is another side to the story. Antibody-drug conjugates are not superior to regular monoclonal antibodies in every aspect. Their significant improvement in drug efficacy is achieved by sacrificing their uniformity and stability. Nowadays, the most mature antibody and toxin coupling technologies are all working on enhancing these two features.
So far, four antibody-drug conjugates have made their way into the US market. In the meanwhile, more than 85 ADC drugs are under development.
Antibody-drug conjugates are made of antibodies, payload toxins, and linkers. The antibody can bind with the target antigen on the surface of tumor cells. Afterward the tumor cells engulf the ADC and release the toxic payload through lysosomal degradation. Toxins then destroy DNA or inhibit division, and eventually kill the tumor cells.
Nowadays, four companies have a clear leg up against its competitors and taken the lead position in the ADC field. They are Seattle Genetics, ImmunoGen, Immunomedics, and Genentech under Roche.
Seattle Genetics, founded in 1998 and listed in Nasdaq in 2001, has been leading the ADC race. It specifically focuses on the research and development of antibody-drug conjugates since its birth. It is also the first company to bring an ADC therapy to the market in the modern ADC era. Its Adcetris, targeted at CD30, was approved by the FDA in August 2011 to treat patients with Hodgkin’s Lymphoma or anaplastic large cell lymphoma. Currently, Seattle Genetics has a total of 10 ADC drugs in various stages of clinical trials. In addition, it has also entered collaborations with a range of biotech and pharma companies, including Celldex, Genentech, AbbVie, Astellas, Bayer, GSK, and Genmab, to co-develop another 14 ADC products.
ImmunoGen, founded in 1981, has been dedicated to developing ADCs for both solid and liquid tumors. Currently, it has 3 drugs in clinical trials and another 6 products under early-stage development. Its core technology has been licensed out and helped a series of companies to develop their own ADCs, including Amgen, Eli Lilly, Novartis, Sanofi, etc. Particularly, Genentech/Roche’s Kadycla has applied their technology.
Immunomedics, founded in 1982, is another heavyweight player in the field of ADCs. Particularly, it is focused on developing new antibody and ADC therapies for cancer patients. Its most well-known candidate IMMU-132, designed to be used in ER and HER2 positive metastatic breast cancer patients, is facing a PDUFA date in the coming January.
Genentech, founded by investor Robert A. Swanson and scientist Herbert Boyer, is the pioneer in recombinant protein production. In 2009, it was acquired by Roche with a total of $46.8 billion. Armed with a range of best-selling drugs, including Rituximab, Herceptin, Avastin, etc., Genentech is also a leader in the field of monoclonal antibody therapy.
To fully explore the potential of antibody drugs, Genentech also joined the race to develop new ADCs. At present, it has successfully brought one product, Kadycla, to the market. This drug was approved for breast cancer patients in February 2013. In addition, it is also actively developing another 9 clinical trial staged candidates.
Abzena, formerly Polytherics, was co-founded by Imperial College and UCL in 2001. It was later merged with several other companies and renamed as Abzena. The company is equipped with a unique technology, ThioBridge, which can increase the uniformity and stability of ADC drugs. In addition, Abzena also specializes in antibody humanization and de-immunization.
Concortis is committed to developing next-generation antibody-drug conjugates for hard to treat diseases. In 2013, it was taken over by Sorrento Therapeutics with $11.3 million. After the acquisition, Concortis has further enriched its technology platforms. Currently, it possesses two crosslinking technologies, C-Lock and K-Lock, and a fully human antibody library G-MAB. With the goal to become the first-in-class and best-in-class ADC provider, Concortis Biosystem has about 20 preclinical-stage candidates in the pipeline. The company is also planning to initiate four clinical trials shortly.
Other companies worth mentioning include Agensys, Celldex, Progenics Pharmaceuticals, Genmab, Stemcentrx, and Takeda Oncology.
In the face of booming antibody market, China has jumped into the increasingly hot ADC space. A number of well-known pharma companies have been actively deploying their resource into this field and building up their pipelines. At present, the fastest players in China have already arrived at various clinical trial stages, including RemeGen, Bio-Thera Solutions, and Zhejiang Medicine.
RemeGen, founded in 2008, is dedicated to the research and development of innovative medications. Particularly, the company focuses on cancer and autoimmune diseases.
Its self-developed ADC drug, RC48, is the first to get into human studies in China. Currently, it is carrying out Phase I clinical trials. RC48 targets at HER2 and can be used to treat cancers with HER2 overexpression, such as stomach cancer, breast cancer, etc.
Bio-Thera Solutions, founded in 2003, is committed to the development of next-generation innovative antibody drugs and biosimilars to treat cancer, autoimmune diseases, cardiovascular diseases, etc.
BAT8001 is its first ADC. It crosslinks recombinant humanized anti-ErbB2/ Neu/HER2 monoclonal antibody with Maitansine derivatives. In animal models, BAT8001 has shown to completely eradicate gastric and breast cancers with positive HER2 expression in nude mice.
On February 22, 2018, Bio-Thera Solutions registered a Phase III clinical trial for its BAT8001 in advanced HER2 positive breast cancer patients. It has skipped phase II studies and surpassed RC48 from RemeGen, becoming the first ADC entered Phase III clinical trials in China.
Fosun Pharma, WuXi AppTec, Zhejiang Medicine, and Ambrx
In May 2015, Fosun Pharma, Hopu Investment, Everbright Healthcare Investment, and WuXi AppTec announced the joint acquisition of Ambrx. Ambrx, founded in 2003, is a biopharmaceutical company dedicated to developing breakthrough biologics therapies. Its unique Protein Medicine Chemistry technology can introduce non-native amino acids into the protein and enables a site-specific conjugation to generate a single species.
Currently, Ambrx has one clinical-staged ADC drug, ARX778, co-developed with Zhejiang Medicine. It received CFDA clinical approval in March 2017. In October of the same year, it initiated its Phase Ia studies against breast cancer patients. ARX788 was also greenlighted by FDA for clinical trials back on August 17, 2016. Its Phase I clinical trials are also ongoing in Australia and New Zealand.
3SBio, founded in 1993, is one of the leading pharmaceutical companies in China. The company is committed to discovering and developing innovative treatments primarily in five fields, including oncology, autoimmune diseases, nephrology, metabolism, and dermatology.
On October 12, 2015, 3SBio struck a deal with Alteogen and received the exclusive right to develop, produce, and commercialize its ALT-P7, an ADC drug targeted at HER2. ALT-P7 was developed based on NexMab, Alteogen’s proprietary drug and antibody coupling platform. In late August 2017, Alteogen announced it is going to start a Phase I clinical trial for ALT-P7 in HER2-positive breast cancer patients at the Samsung Medical Center.
Livzon MabPharm was co-founded by Livzon and Joincare Pharmaceutical in July 2017. The company is devoted to the research and development of novel monoclonal antibody drugs. Up to now, a total of seven products are under development.
Its TNF-alpha monoclonal antibody is the fastest development, currently undergoing phase II clinical trials. In addition, Livzon MabPharma has started a series of collaboration to further strengthen its pipeline. In 2014, Livzon MabPharma has entered a strategic agreement with Epirus to co-develop 5 biosimilars across the globe. In 2016, it joined forces with AbCyte Therapeutics to advance the individualized cell therapy platform based on multifunctional antibodies.
Besides, Livzon MabPharm has penned a deal with MabPlex. Under the agreement, MabPlex will provide a range of services to help Livzon MabPharma to develop its anti-HER ADC drug, ranging from toxin selection to manufacturing to IND application.
Jiangsu Hengrui Medicine
In 2011, Hengrui Medicine, the leader of Chinese innovative drug discovery, entered the field of ADCs. Since then, it has made significant progress. Its innovations primarily focus on linkers, cytotoxic drugs, and its endocytic antibody target selections. So far, its SHR-A1201, the biosimilar to Kadcyla, is the first innovative ADC to apply for clinical trials in China. It was approved in September 2016.
Furthermore, Hengrui has also developed the first c-met antibody drug conjugate, SHR-A1403, in China. This product has applied a site-specific linkage technology, thus enabling more precisely control of the drug and toxin ratio.
Zhejiang Zova Biotherapeutics is exclusively focused on the research and development of antibody-drug conjugates. It has inked a collaboration with Concortis Biosystem and introduced the latter’s advanced ADC platform.
Currently, the most promising candidate under the company’s pipeline is ZV05-ADC. The company has applied both K-Lock and C-Lock technologies to construct this new generation ADC. So far, it has shown good tumor-killing capabilities in the in-vitro screening results. Furthermore, it has also displayed strong safety without obvious side effects in acute toxicity tests in rats.
Another star in the company’s portfolio is ZV0201, a biosimilar to Kadcyla. Compared to the latter, it has exhibited higher anti-tumor activities in both in vitro experiments and N87 mouse gastric cancer model studies.
Other Chinese companies in this space:
Hangzhou DAC biotech
Its DP303C, developed for gastric cancers, has been granted an orphan drug certificate from the FDA
In April 2014, Hisun has signed an agreement with Ambrx to co-develop ADCs using its Unnatural Aminoacid technology.
Its ADC product MRG003 was submitted for IND in August 2017. The composition of the drug is predicted to be the anti-EGFR antibody linked to the small molecule toxin CPT-11.
It is currently developing HER2-TM1.
It is currently developing T-TM1 and CD30-TM1.
The company is committed to the development of new generation of ADCs.
In January 2017, the company has penned a deal with Ambrx to develop ADCs for cancer patients.
(2) The company also acquired the commercial right of ARX788 in China.
Sunshine Guojian is equipped with an ADC drug coupling Trastuzumab and Maitansine. It has submitted to the CFDA for clinical approval in the end of 2016.
(1) Kelun’s third generation HER2 ADC, A166, is the first to apply Lysine specific conjugation.
(2) The product is designed to treat HER2 positive breast, gastric, and various other solid tumors.
(3) It has been approved for clinical trails in both US and China.
Over the last few years, antibody-drug conjugates have continued to deliver a steady flow of positive news. Specifically, the already-approved ADCs have been actively exploring new indications. As a result, their sales revenues have climbed higher. Among them, Kadcyla is the outright winner. In 2017, it has raked in a total of $960 million globally, approaching the blockbuster status. Adcetris came in second place. So far, it has been sold to 47 countries across the globe and bagged in $582.3 million worldwide last year.
Over the next decade, it is predicted that another 7-10 antibody-drug conjugates will come to market. The total market value is expected to reach $10 billion by 2024.
Jin Zhang M.D., Ph.D is project and account manager at LakePharma, and editor at The Pharmaceutical Consultant.