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Jin Zhang M.D., Ph.D is editor at The Pharmaceutical Consultant.
Jin Zhang provides an overview of China's major bispecific antibody developers.
Monoclonal antibody therapies have become the rising star in the modern pharmaceutical industry. Riding on this steady upward trend, bispecific antibodies have also come to light. According to a report from Market Watch published in June of 2014, the market is predicted to reach a total of $4.4 billion by 2023.
Bispecific antibodies consist of two types of antibodies recognizing two specific antigen sites. This enables them to interact with both the targeted cells and functional cells at the same time, enhancing their killing capabilities. Compared to monoclonal antibodies, they can be 100 to 1000 times more effective, whereas the dose is only 1/2000 of the former.
The first bispecific antibody approved in the world was Removab from Fresenius, designed to treat malignant ascites. However, it has not been green-lit by the FDA and is only approved in Europe. So far, the only FDA-accepted bispecific antibody is Amgen’s Blinatumomab. This was given the go-ahead to treat patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia on July 11, 2017.
With bispecific antibodies moving into the spotlight, pharma giants are shouldering their way into this tough contest. According to Zhongtai Securities, a total of $4 billion has been invested in this field so far.
The design of a bispecific antibody greatly influences its success down the line. So far, more than 30 platforms have been developed. The following are among the most popular.
BiTE (bispecific T cell Engager) - Amgen
Amgen’s BiTE technology was originally acquired from Micromet and the former’s first bispecific antibody Blincyto was created using this platform. BiTE is designed to bind CD3 on the T cells and an antigen specific for tumor cells at the same time, thus recruiting activated T cells directly to malignant cells and increasing the killing effects. Blincyto is structured to bind with CD3 and also CD19 on malignant B cells to treat patients with B-cell precursor acute lymphoblastic leukemia.
CrossMab - Roche
On the basis of knobs-into-holes, Roche has developed the CrossMab platform. The team switched the CH1 and CL in the Fab region and solved the light chain mismatch problem. In addition, the company has acquired Dutalys, an Austrian biotech company, for$489 million and bagged its bispecific antibody platform, DutaMab. This has further strengthened Roche’s presence in this field.
Other honorable mentions in this space include DART, tandAB, and Bi-nanobody.
Four bispecific antibody platforms have been developed in China. They are the iTAB from Generon Biomed, DPL from Adagene, Ybody from YZY Bio, and FIT-Ig from EpimAb Biotherapeutics.
Amgen is a major player in the bispecific antibody field. Its Bincyto was the first bispecific antibody approved by both FDA and EMA. It was based on the BiTE platform and designed to recognize both CD19 on tumor cells and CD3 on T cells. In phase III TOWER studies, Bincyto has shown to significantly improve the survival period of adult patients with relapsed or refractory (R/R) Ph+ B-cell precursor ALL.
Amgen is also co-developing a bispecific antibody AMG570 with AstraZeneca, designed to target both BAFF and ICOS ligand. This is currently in phase I clinical trials.
In December 2014, Roche acquired the DutaMab bispecific antibody platform from Dutalys for $133.75 million upfront and additional $355 million in milestones. With this deal, the company complemented its own CrossMab technology and further strengthened its capability in bispecific antibody development.
RG7716 is Roche’s most advanced bispecific antibody in the pipeline. In February 2018, it successfully completed its Phase II clinical trials treating patients with vision loss from diabetic macular edema. The results show it has achieved clinically meaningful and significant improvements. RG7716 is the first bispecific designed for retinal eye diseases. Thanks to these promising results, phase III studies are slated to start soon.
Janssen Biotech (Johnson & Johnson)
In November 2017, Janssen penned a deal with Zymeworks and received the right to the latter’s Azymetric and EFFCT platforms to develop six bispecific antibodies.
Zymeworks is dedicated to the discovery, development, and commercialization of next-generation multifunctional therapies. Its Azymetric technology can transform monoclonal antibodies into bispecific antibodies, thus prohibiting multiple signal pathways and recruiting immune cells to the right site simultaneously. Its EFFCTTM platform, on the other hand, is a library of modified Fc regions. It can modulate immune responses through modifications on the Fc. This technology is compatible with both traditional monoclonal antibodies and the Azymetric platform.
In January 2015, GSK formed a strategic collaboration with Adimab to co-develop bispecific antibodies. Under this agreement, the latter will apply its unique full-length bispecific platform to select stable candidates for further development.
In October 2015, Eli Lilly inked a deal with Chinese Biotech company Innovent Bio to co-develop and commercialize three bispecific antibodies against PD-1. According to the contract, Eli Lilly acquired the production and sales right outside China and related areas.
MacroGenics is a major player in the field of bispecific antibodies. Relying on its strong technology platforms, it has formed strategical collaborations with a series of pharma companies in the field, including Janssen, Takeda, Pfizer, and Merck.
In December 2014, it sealed a deal with Janssen, granting the latter the right to develop its MGD011 for multiple B-cell malignancies. Under the agreement, MacroGenics is eligible to receive a $50 million upfront payment, $75 million shares, and up to $575 million milestone payments down the line.
Not long ago, MacroGenics inked a $500 million agreement with Takeda and entered an alliance to develop its DART candidate MGD010 treating autoimmune disorders.
A total of 15 Chinese pharma companies are actively developing bispecific antibodies. Other than the well-known companies Hengrui Medicine and Livzon, a range of young start-ups have jumped into the field, including Innovent Bio, AlphaMab, and Junshi Pharma.
YZY Bio is committed to developing a new class of innovative antibodies to treat cancers and is leading the bispecific antibodies race in China.
The company has developed YBOY, a unique asymmetrical bispecific antibody technology. It is able to produce full IgG bispecific antibodies, thus making the production and PD/PK similar to that of monoclonal antibodies. In addition, this platform can reduce the dimmer formation through knob-in-hole and salt bridge engineering.
YZY Bio has the highest number of bispecific antibody candidates in the pipeline among all Chinese pharma companies. Its M802, designed to target HER2 and CD3 to treat breast cancer patients, is its most advanced contender. So far, it has completed druggability studies and pilot-scale process development. M802 received its clinical approval from the CFDA on September 29, 2017, marking the first China self-developed bispecific antibody in the clinical trials.
Previous results have indicated that M802 is especially powerful when killing cancer cells with high levels of HER2 expression. Its effect is superior to Herceptin. In addition, it has also shown great results in tumors with a low to mid-level of HER 2 expression.
And there is more to come. YZY Bio’s second most advanced product M701 has also reached clinical stages, currently under CFDA review. It is designed to bind with both EpCAM and CD3, primarily used to treat malignant ascites patients with EpCAM positive colorectal and ovarian cancers.
EpimAb, one of the youngest companies in the Chinese bispecific antibody field, is also one of the strongest contenders. It has developed FIT-Ig, a proprietary, unique, and efficient platform, that produces bispecific candidates with antibody-like properties.
In June 2016, EpimAb stoked a deal with Innovent Bio granting EpimAb the right to apply FIT-Ig platform in China. Under this agreement, EpimAb is eligible to receive up to $120 million, along with commercial loyalties after listing. EpimAb has also forged alliances with Kymab and WuXi AppTec respectively.
Innovent Bio has built a robust bispecific antibody pipeline and is actively seeking collaborations with well-known companies in the field.
In October 2015, Innnovent landed a deal with Eli Lilly to co-develop three bispecific antibodies against tumors. All three products are derived from Innovent Bio self-developed PD-1 monoclonal antibody. In June 2016, Innovent further penned a collaboration with EpimAb to acquire the latter’s FIT-Ig.
IBI302 is currently its most famous candidate, designed to treat various macular diseases and solid tumors. It targets both the VEGF and complement system and has shown good anti-angiogenic and anti-complement effects.
BenHealth, founded in 2015, is committed to developing innovative tools and technical solutions for cell and biopharmaceutical therapies. Currently, a total of seven bispecific antibodies are under development in its pipeline. Among them, CD3-MUC1 is leading the development, with a total of eight clinical studies reaching phase II. The company is actively testing it impacts in various solid tumors, including gastric, kidney, and colorectal cancers, when combining with activated CIK.
Generon Biomed has developed a unique bispecific platform iTab, designed to produce bispecific antibodies directly activating T cells. It can simultaneously bind with CD3 and a specific tumor surface antigen, recruiting and activating T cells at the site of tumors.
Based on this platform, the company has developed three bispecific antibodies in the field of immune-oncology. At present, A-337, designed to target EpCAM, is the most advanced candidate, reaching phase I clinical trials.
PersonGen and Anke Biotechnology
PersonGen, shorted for Personalized Gene Therapy, is dedicated to revolutionizing the treatment in the field of cancer immunology. Its CD3-CD138 bispecific antibody, developed on the basis of BiTE platform, has shown good results in multiple myeloma.
The company also focuses on the development of CAR-T and CAR-NK therapies.
AlphaMab, founded in 2009, is equipped with a unique bispecific platform, Charge Repulsion Improved Bispecific (CRIB). This technology is able to manipulate the charge network among various Fc bonds, thus greatly increasing the formation of heterodimers and reducing homodimers at the same time. Relying on this platform, four different bispecific antibodies are under development, including KB026, KN052, KN046, and KN043.
In April 2014, Hisun has successfully landed a deal with Ambrx to develop and commercialize bispecific antibodies developed on the latter’s platform. Under this agreement, Hisun is eligible to receive commercial rights within China.
SYSVAX, founded in 2018, has established a unique bispecific platform, called Nanobody Bispecific T-cell Engager (nanoBiTE). It combines two nanobodies, with each arm recognizing T cell and tumor cell antigens respectively. It is currently the smallest bispecific antibody structure, just one fifth of the normal antibody molecule.
From the first half of 2015, Hengrui began to establish its own bispecific antibody platform. So far, three candidates are under development.
In January 2016, Livzon Pharm acquired 40% share of AbCyte Therapeutics with a $3 million investment. Livzon is currently developing a number of monoclonal and bispecific antibodies.
Other notable companies in the field of bispecific antibody in China include Adagene, Henlius, and ComBio.
Jin Zhang M.D., Ph.D is project and account manager at LakePharma, and editor at The Pharmaceutical Consultant.