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▎The content team editor of WuXi AppTec.
Last week, the US FDA accelerated the approval of the bispecific antibody Rybrevant (amivantamab-vmjw) developed by Johnson & Johnson's Janssen Company for the treatment of EGFR exon 20 Patients with non-small cell lung cancer (NSCLC) with insertion mutations.
For this patient group, this is the first precision therapy approved by the FDA.
For the field of bispecific antibody development, this approval also represents a milestone.
This is the first time the FDA has approved a bispecific antibody therapy targeting different tumor antigens.
Today, the US FDA has issued guidelines for the development of bispecific antibodies, providing guidance and suggestions for the industry to develop this innovative treatment model.
Bispecific antibodies, as the name suggests, are antibodies that can specifically bind to two different antigens.
The feature that it can bind to different antigens gives this class of molecules great flexibility.
Currently, hundreds of bispecific antibodies have entered the clinical development stage.
Previously, Amgen's bispecific T cell binding device (BiTE) Blincyto (blinatumomab) has been approved by the FDA to treat blood cancers.
The bispecific factor IXa and factor X antibody Hemlibra developed by Roche also received FDA approval in 2018.
The approval of Rybrevant, which targets EGFR and MET, represents another mode of action of bispecific antibodies that has been recognized by regulatory agencies.
Today, WuXi AppTec's content team will combine public information to introduce this new drug development field that is expected to usher in an explosion.
Image source: The mode of action of the 123RF bispecific antibody connects two different cells.
In the field of bispecific antibody development, the first and most common type of antibody is the bispecific linking two different cells together.
Antibodies, one end of these antibodies binds to a specific antigen on the surface of a cell, and the other end binds to a specific antigen on the surface of another cell, thereby bringing two different cells closer together and promoting interaction between them .
One of the representatives of this bispecific antibody is the T cell engager.
▲ A bispecific antibody connecting two different cells (picture source: reference [3]) Amgen's Blincyto is this type of molecule, and it is also the first bispecific antibody approved by the FDA.
One end of it binds to the CD19 antigen expressed on the surface of B cells, and the other end binds to the CD3 receptor on the surface of T cells, thereby recruiting T cells to the vicinity of cancer cells and promoting them to kill cancer cells.
Today, dozens of bispecific antibodies that bind to CD3 receptors are in clinical trials.
They are used as immunotherapies to treat blood cancers.
In recent years, at the annual meeting of the American Society of Hematology (ASH), a variety of bispecific antibodies Sex antibodies have shown good results in the treatment of different blood cancers.
Compared with CAR-T therapy that also uses T cells to kill cancer cells, T cell adapter therapy has greater flexibility.
At the ASCO annual meeting to be held this year, there are also a variety of T cell adapters that will report the latest clinical results.
For example, today, Janssen announced that its bispecific antibody teclistamab, which targets B cell maturation antigen (BCMA) and CD3, is used in the treatment of relapsed/refractory multiple myeloma (R/R MM) that has received various previous treatments.
Positive results were obtained in the patient's phase 1 clinical trial.
At a median follow-up time of 6.
1 months, the total remission rate of patients receiving the recommended dose of the phase 2 clinical trial reached 65%, and 40% of the patients achieved complete remission, and the median duration of remission had not yet been reached.Another potential "first-in-class" bispecific antibody therapy, talentamab, developed by the company that targets GPRC5D, achieved a 70% overall response rate, including 60%, in the Phase 1 clinical trial for the treatment of R/R MM patients.
Very good partial relief (VGPR).
Due to the flexibility of bispecific antibodies, by changing the antigens it can bind, it can be used to recruit other immune cells including innate killer cells (NK cells), and it can also be used to target antigens expressed by solid tumors.
At present, T cell adaptors targeting HER2, PSMA and other solid tumors expressing antigens are already in the clinical development stage.
The recently approved Rybrevant, which targets different antigens on the same cell surface, represents another mode of action for bispecific antibodies, which allows bispecific antibodies to bind to different proteins expressed on the same cell surface.
For example, Rybrevant can bind to EGFR and MET.
Although the strategy of targeting cancer-related tyrosine receptor kinase (RTK) has achieved good results in the treatment of various cancers, the development of drug resistance has always been one of the main factors limiting the efficacy of these targeted therapies .
An important mechanism for drug resistance is to increase the expression of other RTKs to replace the inhibited signaling pathways.
For example, in patients with non-small cell lung cancer, activation of the MET signaling pathway can make patients resistant to EGFR inhibitors.
As a bispecific antibody that targets both EGFR and MET, Rybrevant can block both signal pathways at the same time.
It can also further kill cancer cells through antibody-dependent cell-mediated cytotoxicity (ADCC).
▲Bispecific antibodies targeting different antigens on the same cell surface (picture source: reference [3]) A variety of bispecific antibodies using this mechanism have also entered the clinical development stage, including those that target both CD19 and CD22 Bispecific antibodies, as well as bispecific antibodies targeting HER2 and HER3, etc.
Targeting different epitopes of the same antigen Another bispecific antibody design model is to allow it to bind to different epitopes of the same antigen.
The HER2 targeting bispecific antibody zanidatamab developed by Zymeworks is one such example.
It can bind to two non-overlapping epitopes on HER.
This unique design allows the same HER2 receptor to bind to two antibodies.
This mechanism of action can promote the aggregation, internalization and degradation of HER2 receptors, and improve the efficiency of blocking HER2 signaling.
In addition, it can enhance antibody-mediated cytotoxicity.
It has been approved by the FDA as a breakthrough therapy for the treatment of HER2-positive biliary tract cancer.
It is used in combination with chemotherapy to achieve a confirmed objective response rate of 54% in the first-line treatment of HER2-positive gastroesophageal adenocarcinoma (GEA) in clinical trials.
BeiGene has reached an agreement with Zymeworks to jointly develop this innovative treatment.
▲Zanidatamab has a unique mechanism of action (picture source: Zymeworks official website) U.
S.
FDA guidelines for the development of bispecific antibodies Today, the U.
S.
FDA issued guidelines to help the pharmaceutical industry and other stakeholders develop bispecific antibodies, which are bispecific Guidance is provided on multiple aspects of sexual antibody development.
According to the FDA, in general, the development of bispecific antibody therapy is similar to the development of monoclonal antibody therapy in many aspects, but due to the particularity and complexity of its structure, bispecific antibodies may require targeted guidance.
Last week, the US FDA accelerated the approval of the bispecific antibody Rybrevant (amivantamab-vmjw) developed by Johnson & Johnson's Janssen Company for the treatment of EGFR exon 20 Patients with non-small cell lung cancer (NSCLC) with insertion mutations.
For this patient group, this is the first precision therapy approved by the FDA.
For the field of bispecific antibody development, this approval also represents a milestone.
This is the first time the FDA has approved a bispecific antibody therapy targeting different tumor antigens.
Today, the US FDA has issued guidelines for the development of bispecific antibodies, providing guidance and suggestions for the industry to develop this innovative treatment model.
Bispecific antibodies, as the name suggests, are antibodies that can specifically bind to two different antigens.
The feature that it can bind to different antigens gives this class of molecules great flexibility.
Currently, hundreds of bispecific antibodies have entered the clinical development stage.
Previously, Amgen's bispecific T cell binding device (BiTE) Blincyto (blinatumomab) has been approved by the FDA to treat blood cancers.
The bispecific factor IXa and factor X antibody Hemlibra developed by Roche also received FDA approval in 2018.
The approval of Rybrevant, which targets EGFR and MET, represents another mode of action of bispecific antibodies that has been recognized by regulatory agencies.
Today, WuXi AppTec's content team will combine public information to introduce this new drug development field that is expected to usher in an explosion.
Image source: The mode of action of the 123RF bispecific antibody connects two different cells.
In the field of bispecific antibody development, the first and most common type of antibody is the bispecific linking two different cells together.
Antibodies, one end of these antibodies binds to a specific antigen on the surface of a cell, and the other end binds to a specific antigen on the surface of another cell, thereby bringing two different cells closer together and promoting interaction between them .
One of the representatives of this bispecific antibody is the T cell engager.
▲ A bispecific antibody connecting two different cells (picture source: reference [3]) Amgen's Blincyto is this type of molecule, and it is also the first bispecific antibody approved by the FDA.
One end of it binds to the CD19 antigen expressed on the surface of B cells, and the other end binds to the CD3 receptor on the surface of T cells, thereby recruiting T cells to the vicinity of cancer cells and promoting them to kill cancer cells.
Today, dozens of bispecific antibodies that bind to CD3 receptors are in clinical trials.
They are used as immunotherapies to treat blood cancers.
In recent years, at the annual meeting of the American Society of Hematology (ASH), a variety of bispecific antibodies Sex antibodies have shown good results in the treatment of different blood cancers.
Compared with CAR-T therapy that also uses T cells to kill cancer cells, T cell adapter therapy has greater flexibility.
At the ASCO annual meeting to be held this year, there are also a variety of T cell adapters that will report the latest clinical results.
For example, today, Janssen announced that its bispecific antibody teclistamab, which targets B cell maturation antigen (BCMA) and CD3, is used in the treatment of relapsed/refractory multiple myeloma (R/R MM) that has received various previous treatments.
Positive results were obtained in the patient's phase 1 clinical trial.
At a median follow-up time of 6.
1 months, the total remission rate of patients receiving the recommended dose of the phase 2 clinical trial reached 65%, and 40% of the patients achieved complete remission, and the median duration of remission had not yet been reached.Another potential "first-in-class" bispecific antibody therapy, talentamab, developed by the company that targets GPRC5D, achieved a 70% overall response rate, including 60%, in the Phase 1 clinical trial for the treatment of R/R MM patients.
Very good partial relief (VGPR).
Due to the flexibility of bispecific antibodies, by changing the antigens it can bind, it can be used to recruit other immune cells including innate killer cells (NK cells), and it can also be used to target antigens expressed by solid tumors.
At present, T cell adaptors targeting HER2, PSMA and other solid tumors expressing antigens are already in the clinical development stage.
The recently approved Rybrevant, which targets different antigens on the same cell surface, represents another mode of action for bispecific antibodies, which allows bispecific antibodies to bind to different proteins expressed on the same cell surface.
For example, Rybrevant can bind to EGFR and MET.
Although the strategy of targeting cancer-related tyrosine receptor kinase (RTK) has achieved good results in the treatment of various cancers, the development of drug resistance has always been one of the main factors limiting the efficacy of these targeted therapies .
An important mechanism for drug resistance is to increase the expression of other RTKs to replace the inhibited signaling pathways.
For example, in patients with non-small cell lung cancer, activation of the MET signaling pathway can make patients resistant to EGFR inhibitors.
As a bispecific antibody that targets both EGFR and MET, Rybrevant can block both signal pathways at the same time.
It can also further kill cancer cells through antibody-dependent cell-mediated cytotoxicity (ADCC).
▲Bispecific antibodies targeting different antigens on the same cell surface (picture source: reference [3]) A variety of bispecific antibodies using this mechanism have also entered the clinical development stage, including those that target both CD19 and CD22 Bispecific antibodies, as well as bispecific antibodies targeting HER2 and HER3, etc.
Targeting different epitopes of the same antigen Another bispecific antibody design model is to allow it to bind to different epitopes of the same antigen.
The HER2 targeting bispecific antibody zanidatamab developed by Zymeworks is one such example.
It can bind to two non-overlapping epitopes on HER.
This unique design allows the same HER2 receptor to bind to two antibodies.
This mechanism of action can promote the aggregation, internalization and degradation of HER2 receptors, and improve the efficiency of blocking HER2 signaling.
In addition, it can enhance antibody-mediated cytotoxicity.
It has been approved by the FDA as a breakthrough therapy for the treatment of HER2-positive biliary tract cancer.
It is used in combination with chemotherapy to achieve a confirmed objective response rate of 54% in the first-line treatment of HER2-positive gastroesophageal adenocarcinoma (GEA) in clinical trials.
BeiGene has reached an agreement with Zymeworks to jointly develop this innovative treatment.
▲Zanidatamab has a unique mechanism of action (picture source: Zymeworks official website) U.
S.
FDA guidelines for the development of bispecific antibodies Today, the U.
S.
FDA issued guidelines to help the pharmaceutical industry and other stakeholders develop bispecific antibodies, which are bispecific Guidance is provided on multiple aspects of sexual antibody development.
According to the FDA, in general, the development of bispecific antibody therapy is similar to the development of monoclonal antibody therapy in many aspects, but due to the particularity and complexity of its structure, bispecific antibodies may require targeted guidance.
