Development History and Market Prospects of Bispecific Antibodies

2021-09-22

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With the development and progress of antibody technology, the research and development of bispecific antibodies has shown a good development prospect, which is expected to fill the shortcomings of current therapies in some indications. Recently, Medicilon assisted Biotech’s first bispecific antibody (PD-L1/CD47). ) Apply for clinical application.

With the development of bi-antibody technology, bi-antibody now presents a good development prospect. While major companies are deploying bi-antibody product research and development, they also pay great attention to what needs to be paid attention to and considered in the biological analysis of bi-antibody. Regulations and technical points. The Pharmaceutical Analysis Department of Medicilon Biotechnology is committed to tailoring Case by Case biological analysis methods for customers.

History of Dual Anti-drug Development

Fifty years ago, Nisonoff and colleagues proposed the concept of bispecific antibodies (bsAb). In the following decades, studies confirmed that bispecific antibodies can attract immune cells to tumor sites and induce T cells to kill tumors, providing a new potential immunotherapy method for cancer treatment and diagnosis. As of July this year, more than 200 dual-antibody drugs are in clinical and preclinical research stages.

Schematic diagram of bispecific antibodies in cancer: mechanism of action and potential targets

Reference:
Medicilon assisted Bio-Thera's bispecific neutralizing antibody drug for injection BAT2022 for the treatment of new coronary pneumonia was approved for clinical use
[Medicilon Assist] Bio-Thera's Bispecific Antibody BAT7104 has been Approved for Clinical Trials
The Biological Analysis of Bispecific Atibody

Introduction to Popular Targets of Bispecific Antibodies

There are nearly a hundred ways of combining bispecific antibody targets in the research and development of bispecific antibodies. Compared with the relatively high concentration of monoclonal antibody target selection, bispecific antibody target selection is more diversified. The top ten targets in the number of bispecific antibodies developed are CD3, PD-L1, CD47, CD20, EGFR, etc.

CD3 is currently the most popular choice for dual antibody targets, and it has the largest number of combinations with other targets. In addition to CD3, PD-1, PD-L1 and CD47 are the targets with a larger number of bispecific antibodies. For example, Medicilon assisted Biotech’s first bispecific antibody BAT7104 to apply for clinical application. BAT7104 is the PD-L1/CD47 bispecific antibody.

The development of PD-1/PD-L1 immune checkpoint inhibitors has brought revolutionary treatment strategies to cancer. It has always been a cutting-edge research direction in the field of tumor immunity, and it is also the first choice for most innovative pharmaceutical companies in China to open the field of immunotherapy .

CD47 is a five-pass transmembrane protein with a molecular weight of about 45-55kDa and belongs to the immunoglobulin superfamily. CD47 is highly expressed in most tumor cells, such as myeloma, Leyome sarcoma, leukemia, non-Hodgkin’s lymphoma, breast cancer, osteosarcoma and hepatocellular carcinoma; it is a mechanism of cancer immune escape and belongs to a kind of A new type of immune checkpoint is one of the popular targets for tumor immunotherapy research and development.

CD47/PD-L1	Solid tumors and hematological tumors	Phase I
PD-1/CD47	Malignancies	Phase I
CD47/CD20	B-cell Non-Hodgkin’s Lymphoma	Phase I
CD47/CD19	Haematologicalmalignancies	Phase I
SIRPα-Fc-CD40L	Ovarian Cancer	Phase I

Table 1: Clinical research progress of Bispecific antibodies targeting CD47, as of March 2021

Overview of Bispecific Antibody Drug Market

Antibody drugs are one of the important development directions of immunotherapy drugs. Compared with monoclonal antibodies, bispecific-antibody drugs have advantages in terms of improved efficacy and reduced side effects. They are called “second-generation” immunotherapy drugs, and their research and development has attracted the attention of many pharmaceutical companies around the world.

There are high barriers to the research and development of dual antibody drugs, but the future market space is vast. Therefore, the number of companies entering the field of dual antibodies is increasing. In the foreign market, the main R&D companies for dual antibody drugs include Roche, Amgen, MacroGenics, Xencor, Genmab, AstraZeneca, etc. In the domestic market, the companies that have deployed the dual-antibody drug market are mainly Corning Jerry, BeiGene, Anmai Bio, Xinda Bio, Kangfang Bio, Wuhan Youzhiyou, Hengrui Medicine, Sichuan Baili, etc.

Globally, there are more than 200 bispecific-antibody drugs in clinical and pre-clinical stages, of which tumor treatment drugs dominate, accounting for about 80% of the total, and other disease treatment drugs are less developed.

There are currently four dual-antibody drugs approved for marketing, namely Trion Pharma’s Removab, Amgen’s Blincyto, Roche’s Hemlibra, and Janssen’s Rybrevant; among them, Removab targets T cell surface antigen receptor CD3 and cancer cell marker EpCAM; Blincyto targets CD3 and CD19; Hemlibra targets FIX and FX; Rybrevant targets EGFR-Met. Removab is the world’s first dual-antibody drug approved for marketing and the world’s first dual-antibody drug to be delisted. Rybrevant is the first targeted therapy for non-small cell lung cancer approved by the FDA in May this year. Currently, only Hemlibra has entered the domestic market. Hemlibra is mainly used for the treatment of hemophilia. It has obvious advantages in terms of efficacy, half-life, and convenience of administration, and the market demand is rapidly increasing. As Hemlibra enters the domestic market, the market awareness of bispecific-antibody drugs is constantly improving.

Outlook

A bispecific antibody is an antibody protein with multiple domains. It has multiple different binding sites and a more complicated mechanism of action. These add more consideration points to the design of the analysis method of the bispecific antibody drug. For more complexity, the molecular forms that need to be measured include total, free, total bound, and partial bound. The analysis of these forms requires the consideration of Case by Case.

The Pharmaceutical Analysis Department of Medicilon Biotechnology is committed to tailoring Case by Case bioanalysis methods for customers, and uses advanced technology platforms to complete high-quality and efficient research services. Medicilon Biotechnology Drug Analysis Department flexibly uses ELISA, ECL, TRFIA, CLIA, IF, IP, CoIP, qPCR, FACS, ELISpot, H-ELISA, enzyme activity and other methods to support cutting-edge biological drugs such as proteins and antibodies ( PK/TK/Immunogenicity (Total ADA& Nab)/Biomarker&Cytokine, etc. in early development, preclinical and clinical stages of drugs such as monoclonal antibodies, bi- or multispecific antibodies, antibody fragments), ADCs, peptides, nucleic acids, vaccines and cell gene therapy Research evaluation. Currently, a number of ADC drugs involving Her2, Trop2, Muc1 and other targets have been supported, and popular targets such as EGFR, PCSK9, IL-17A, IL-6, IL-23, VEGF, CD47, TNF-α, CD20, TIGIT, etc. And 4-1BB, PD1, PDL-1, CTLA4 and other immune checkpoint monoclonal antibodies or polyclonal drugs, CAR-T and CAR-NK targeting different targets, as well as various fusion proteins, oncolytic viruses, nucleic acids and many other Involved in the research work of peptide drugs in different stages of diabetes, cardiovascular, bone, tumor and other related diseases.

Reference: Yan Yang, et al. Potential Role of CD47-Directed Bispecific Antibodies in Cancer Immunotherapy. Front Immunol. 2021 Jul 8;12:686031.

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