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    Home > Active Ingredient News > Drugs Articles > 2021 DIA Annual Meeting | Controversy between monoclonal antibodies and double antibodies-can double antibodies replace monoclonal antibodies?

    2021 DIA Annual Meeting | Controversy between monoclonal antibodies and double antibodies-can double antibodies replace monoclonal antibodies?

    • Last Update: 2021-06-05
    • Source: Internet
    • Author: User
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    In recent years, as the pharmaceutical industry continues to deepen the research on the structure and biosynthesis technology of dual-antibody drugs, the global dual-antibody drug market has ushered in an explosive period.
    Double antibodies are developed based on monoclonal antibodies and are regarded as the second-generation antibody therapy for tumor treatment.

    In recent years, as the pharmaceutical industry continues to deepen the research on the structure and biosynthesis technology of dual-antibody drugs, the global dual-antibody drug market has ushered in an explosive period.
    Double antibodies are developed based on monoclonal antibodies and are regarded as the second-generation antibody therapy for tumor treatment.

    In the future, can double-antibody drugs be able to replace monoclonal antibody drugs and be even better in terms of effectiveness and safety? On May 22, the 2021 DIA Annual Meeting discussed this topic.

    According to Yang Nong, assistant to the dean of Hunan Cancer Hospital, director of the Department of Medical Oncology, and director of the Department of Pulmonary and Gastrointestinal Oncology, the concept of dual antibodies emerged in 1960.
    In the age of immunotherapy, dual antibodies emerged.
    It is reported that there are currently four dual-antibody drugs on the market worldwide (Removab delisted in 2017), and more than one hundred dual-antibody drugs are in the international multi-center clinical stage.
    From the perspective of indications, most double-antibody drugs choose tumors as indications, with tumor indications accounting for close to 90%, of which solid tumor indications account for 59%, hematological tumors accounting for 29%; followed by autoimmune diseases.
    It accounts for about 8%; other indications include ophthalmic diseases (AMD), rare diseases (hemophilia), etc.

    (1) The difference between monoclonal antibodies and double antibodies

    (1) The difference between monoclonal antibodies and double antibodies

    Bispecific Antibody (bsAb, Bispecific Antibody) is a new type of second-generation antibody that has two specific antigen binding sites and can interact with target cells and functional cells at the same time, thereby enhancing the killing of target cells.

    Compared with monoclonal antibodies, double antibodies add a specific antigen binding site, so they have stronger specificity, more accurately target tumor cells and reduce off-target toxicity.
    Specifically, there are three main advantages of double antibodies, including:

    (1) The two antigen binding sites can bind to tumor cells and immune cells, redirect immune cells, recruit immune cells around the tumor cells, and enhance the lethality of the tumor;

    (2) Two different signal pathways can be blocked at the same time to enhance cell killing toxicity;

    (3) After binding to two different cell surface antigens, relatively speaking, it may potentially increase the binding specificity and reduce the side effects caused by off-target.

    Figure 1: The difference between a monoclonal antibody and a double antibody (BiTE)

    Figure 1: The difference between a monoclonal antibody and a double antibody (BiTE)

    (2) Combination therapy of double antibodies and monoclonal antibodies

    (2) Combination therapy of double antibodies and monoclonal antibodies

    In addition to its superior efficacy over monoclonal antibodies, double antibodies are expected to reduce the incidence of high adverse events in combination therapy.
    Combination therapy with monoclonal antibodies is an important direction of clinical use of drugs.
    The combination therapy of ipilimumab (CTLA-4) and nivolumab (PD-1) launched by BMS can greatly improve the ORR of subjects.
    In the United States, the FDA has approved the simultaneous use of nivolumab and ipilimumab for the first-line treatment of renal cell carcinoma (RCC) (April 2018), and high microsatellite instability (MSI-H) or dMMR ( Second-line treatment for colorectal cancer (CRC) with mismatch repair defects (July 2018).

    However, the combination therapy has always been accompanied by a significant increase in dose-limiting treatment-related toxicity (TRAE) while increasing its anti-tumor activity, resulting in unsatisfactory safety.
    In a Phase III clinical study called CheckMate 067, the proportion of grade 3-4 adverse reactions in the PD-1 monotherapy group was 22%, and the proportion of grade 3-4 adverse reactions in the CTLA-4 monotherapy group was 28.
    %, and the rate of grade 3-4 adverse reactions in the combined drug group (O drug + Y drug) increased to 59%.

    The double antibody is expected to retain the efficacy of the combination therapy and establish a safety that is superior to the combination therapy.
    AK104 is a PD-1/CTLA-4 double antibody of Kangfang Biology.
    Clinical studies have shown that the safety of AK104 is equivalent to PD-1 or PD-L1 monotherapy, and is significantly lower than the toxicity of combination therapy.
    The reason may be that AK104 can only bind to tetravalent TIL co-expressing PD-1 and CTLA-4, which is different from peripheral lymphocytes that often lack checkpoint co-expression and only allow bivalent binding, and may therefore better adhere to The cell surface of TIL has a higher functional affinity to lymphocytes in the tumor microenvironment.

    (3) Can the double antibody replace the monoclonal antibody?

    (3) Can the double antibody replace the monoclonal antibody?

    It may be too early to assert that double antibodies can replace monoclonal antibodies in the future.
    There are still many problems with double antibody drugs that need to be overcome one by one, including issues of efficacy, safety and commercialization.

    Clinical problems:

    Efficacy problem: M7824 is not an exaggeration to describe it as "raise a tall building, entertain guests, and the building collapsed".
    M7824 is a dual-antibody drug targeting PD-L1 and TGF-β jointly developed by Merck and GSK.
    At the 2018 ASCO annual meeting, M7824 made its debut.
    The ORR of the total population of second-line treatment of advanced NSCLC reached 27.
    5%, the ORR of PD-L1 positive (≥1%) patients reached 40.
    7%, and the PD-L1 high expression (≥80%) patients The ORR is as high as 71.
    4%.

    However, 2021 can be described as M7824's Waterloo, and a number of clinical failures cast a shadow over M7824.
    On January 15, 2021, M7824 treatment of patients with advanced immune checkpoint inhibitors (ICB) and disease progression after microsatellite instability (MSI-H)/mismatch repair defects (dMMR) solid tumors in the phase II study did not show The anti-tumor activity ended in failure.
    Five days later, M7824 was once again in the Phase III study of NSCLC.
    Phase III clinical interim analysis showed that M7824 could not beat MSD's K drug and failed to reach the preset end point of PFS.
    What's more unfortunate is that in March, the Phase II clinical study of M7824 as a second-line treatment of advanced cholangiocarcinoma failed to reach the preset end point and ended in failure.

    Safety issues: Although dual-antibody drugs are expected to significantly improve the efficacy, their safety issues should not be underestimated, especially the dual-antibody drugs that target CD3 T cell recruitment.
    On May 4, Pfizer announced that its BCMA×CD3 double antibody product Elranatamab has suspended the enrollment of new subjects due to 3 cases of clinically observed adverse reactions to peripheral neuralgia.
    In February of this year, Amgen announced the temporary suspension of clinical studies of three dual-antibody drugs, including AMG596 (EGFR×CD3), AMG701 (BCMA×CD3), AMG673 (CD33×CD3), among which, BCMA×CD3 is the target The reason for the suspension of AMG-701 may be CRS (Cytokine Release Syndrome) or peripheral nerve damage.
    In December 2020, the Odronextamab clinical trial of Regeneron targeting CD3/CD20 was suspended by the FDA, requiring modification of the trial protocol to reduce the side effects of CRS grade 3 or above.

    Commercialization issues:

    The price of double-antibody drugs may be a major bottleneck in their commercialization.
    Take the two dual-antibody drugs on the market, Blincyto and Hemlibra, as examples.
    Blincyto is priced at US$178,000 per two rounds of treatment in the US market, making it one of the most expensive drugs on the market.
    Blincyto's domestic rights and interests belong to BeiGene.
    It was approved for ALL indications in December 2020, and the price has not yet been announced.
    After Hemlibra was approved by the NMPA in 2018, the first domestic company was 8100 yuan/30mg.
    Although it participated in the 2020 medical insurance negotiations, it was ultimately not included in the medical insurance catalog due to price factors.
    In the future, as more dual-antibody drugs are approved for the market, their prices are worthy of continued tracking.

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