Bispecific Antibodies: A Novel Frontier in Cancer Immunotherapy

Bispecific Antibodies

Immunotherapy has shown remarkable results in treating cancer. Monoclonal antibodies have emerged as a standard cancer care option, but the concern for better treatment continues because of their low binding efficiency to target cells. Some tumors exhibit multiple receptors that activate continuous growth, resulting in metastasis and restrain apoptosis. The advances in technology significantly improved the production of antibodies, resulting in enhancements in antibody-targeted therapies. The one approach that has improved mAbs specificity for cancer cells is through the Bispecific antibodies (BsAb) dual binding mechanism.  

Bispecific antibodies come as a novel frontier in the next-generation immunotherapy strategy because they provide high binding specificity and target multiple surface antigen to trigger the immune system to connect with tumor cells, increasing their cytotoxicity directly. With lots of BsAb drugs under trial, researchers have a hope that advancing Bispecific antibodies will result in better treatment options, allowing patients to live a quality life.

What Are Bispecific Antibodies?

Bispecific antibodies are genetically recombined proteins with two binding units to bind different epitopes on the same antigen. These BsAbs have been designed to attain other functions through monoclonal antibodies, such as bridging immune cells and tumor cells for redirected cytotoxicity. The bispecific antibodies allow blocking of two targeted sites on tumor cells━inhibiting growth, facilitate the formation of protein complexes, and promote immune cell response.

Cellular immune cells typically recognize the structure of the abnormal cells and eliminate them by bridging it to cytotoxic T cells through the TCR-MHC-peptide complex. However, malignant cells may avoid the bridging connection by lowering the immunological HLA peptide expression, secreting immune-suppressing chemicals, and generating an unfavorable tumor microenvironment for T-cell infiltration. The fundamental goal of TAA-based, CD3- or CD16-targeting BsAbs is to build fresh, reliable connections between immune cells and cancer cells to increase the effectiveness and scope of T cell and NK cell activity. The global bispecific antibodies market is estimated to be worth $5.6 billion in 2023 and is expected to grow at compounded annual growth rate (CAGR) of 9.5% during the forecast period, according to Roots Analysis.

What Are the Advantages of Bispecific Antibodies?

Some of the benefits of using Bispecific antibodies includes:

  • The benefit of using Bispecific antibodies for treatment is that they are made “off the shelf,” which means they do not require any existing cells from the patient. Therefore, the patient does not have to travel to specific sites and undergo several medical trials before manufacturing modified immune cells.
  • There is a low risk of cytokine release syndrome, a common side effect due to cytokine release into the bloodstream. A recent case study on the mosunetuzumab mechanism of action reported by the Leukemia and Lymphoma Society shows that nearly all cases of CRS last for a short time after the treatment. So, no late-onset or other chronic toxicity was observed after the treatment.
  • Bispecific antibodies have dual specificity; they can bind to molecular payloads and multiple cell surface antigens simultaneously, providing a robust delivery system to transport cytotoxic entities to tumor cells and inhibit growth.
  • Bispecific antibodies can be prescribed as over-the-counter medications and the patient starts taking them the following week. There might be a several-month delay with CAR T. Therefore, these Bispecific antibodies are now essentially a no-brainer for patients who don’t have fast access to a CAR T facility.

Bispecific Antibodies: Revolutionary Therapeutics for Cancer Treatment

In recent times, researchers have emphasized the development of Bispecific antibodies attached to immune system T-cell antigens and cancer cell antigens. The capacity of the cancer cell to discover a different signaling pathway when using monoclonal antibodies may reduce the efficacy of the antibodies to inhibit the cancer cell’s signaling pathway. However, the Bispecific antibody may lessen the tumor’s drug resistance, enhance the anti-cancer impact, and prevent the formation of immune escape pathways, which let cancer cells avoid the body’s immune response by inhibiting two linked signaling pathways on a cancer cell.

As of now, there are several FDA-approved Bispecific antibodies available for the treatment of cancer, including initially approved Catumaxomab BsAb. Over 600 Bispecific antibodies are currently under clinical trial. With the growing interest of pharmaceutical industries in designing promising immunotherapy, the Bispecific industry is expected to grow at a significant pace during the forecast period. Below, we’ve listed some Bispecific antibodies that are approved by the USFDA and EMA to be used for cancer immunotherapy:

    Pharmaceutical Company      Product Name    BsAbs Name      Target 1    Target 2    Indications    Mechanism of Action    Approved By    Date of Approval
      Amgen      Blincyto®      BlinatumomabCD3 (T cell)CD19 (cancer cell)    B-cell precursor acute lymphoblastic leukemia      Blincyto® mechanism of action is the activation of T cells.      FDA and EMA    December 2014
      Immunocore      Tebentafusp®       Kimmtrak CD3 (T cell)  gp100 (cancer cell)         Unresectable or metastatic uveal melanoma       The mechanism of Tebentafusp is the activation of T cells.        FDA and EMA      January 2022
      Janssen       Rybrevant®      Amivantamab EGFR (cancer cell) c-MET (cancer cell)       Non-small cell lung cancer (NSCLC)       The mechanism of action is the Blocking of dual signal pathways.        FDA and EMA      May 2021
      Janssen       Tecvayli ®      Teclistamab CD3 (T cell)  BCMA (cancer cell)       Relapsed or refractory multiple myeloma       The mechanism of action is the activation of T cells.        FDA and EMA      August 2022
        Roche         Lunsumio®        Mosunetuzumab        CD3 (T cell)        CD20 (cancer cell)         Relapsed or refractory follicular lymphoma             mosunetuzumab mechanism of action is the activation of T cell          FDA and EMA        June 2022

What Oncologists Say About Bispecific Antibodies and the Future Possibilities ?

The success of developing Bispecific antibodies for treating relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in children and adults has given a new ray of hope to design more specific drugs. In 2017, the FDA approved the Bispecific antibody drug (Blincyto®) Blinatumomab for treating relapsed or refractory B-cell precursor acute lymphoblastic leukemia. However, after the success of the BsAb, the FDA expanded the approval for the treatment of minimal residual disease-positive B-cell precursors.

  • Jeremy T. Larsen, MD, Hematologic Oncologist, has treated several cancerous patients with BsAb at City of Hope Phoenix. He said, unlike chemotherapy drugs, where toxicity pays back over time, Bispecific antibodies reduce the chances of toxicity, helping patients live a quality life. The development of Bispecific drugs is a breakthrough for the patients.
  • Elizabeth Budde, MD, PhD, Associate Professor in the Department of Hematology & Hematology Cell Transplantation, said to ABC7 in Los Angeles that BsAb is similar to putting a glass on the T-cells so it can recognize one’s lymphoma cells and act on cancerous cells. Examples of Bispecific T-cell engagers (BiTEs) are teclistamab, Blinatumomab, and mosunetuzumab. These T-cell engagers fight B-cell malignancies by binding directly to CD19 protein on cancerous B-lineage cell’s surface and CD3 protein on T-cells. 
  • Dr. Budde states, “the beneficial and detrimental cells are pulled together, with mosunetuzumab acting as a kind of bridge.” Being so close together enables the immunological T-cells that have been activated to identify, target, and eradicate the lymphoma cells specifically.
  • Bispecific antibody therapies include more than just the malignancy and T-cells being close to one another. According to Charles Sentman, Ph.D., of the Geisel School of Medicine at Dartmouth University, activating T-cells causes the release of immune chemicals known as cytokines, which then draw other immune cells—like macrophages and natural killer cells—to the tumor target.

Bispecific Antibodies- The Future of Cancer Immunotherapy

Over the years, antibodies-based immunotherapy has gained attention. With advances in technology and the pharmaceutical sector, more BsAb will be designed by the industrial leaders. The Bispecific antibody therapies will continue to be explored in new therapeutic areas for treating refractor/relapsed cancers, specifically for those with targetable cellular markers. The interest of marketing leaders remains strong, and they may focus on designing more BsAb. Of the above, BsAb is the new frontier oncology treatment.

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