What are bispecific antibodies, the new therapeutic revolution

What are bispecific antibodies, the new therapeutic revolution

Medical oncology has always been made up of small steps. Therapeutic innovations that follow one another, improving the prognosis, reducing side effects, pushing tumors to a standstill while waiting for new drugs that add a new stage to the patient's treatment path. Generations of molecules that follow one another, exploiting innovative mechanisms of action to overcome the limits of the previous ones. To expand the arsenal available to oncologists, and the audience of patients who can benefit from them. One of the most discussed innovations in recent months are bispecific antibodies: synthetic monoclonal antibodies capable of taking the cells of the immune system "by the hand", guiding them towards those of the tumor, and making sure that they perform their function to the fullest. As always in medicine, these are not miracle drugs, but an extremely promising technology that is coming to maturity after decades of research and clinical trials.

A long story

Indeed, research in this field has its roots in the work of the pioneers of modern immunology, who as early as the 1960s had begun to imagine the possibility of engineering antibodies to make them capable of recognizing more than one antigen. Unlike traditional monoclonal antibodies, however, bispecific antibodies are not naturally produced by the immune system, and must therefore be specially synthesized in the laboratory using bioengineering or genetic engineering techniques. And it is only in recent decades that technological advances have made it possible to build molecules of this kind effectively and relatively cheaply, opening the door to human experimentation.

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A bridge between cells

Bispecific antibodies are synthetic antibodies capable of recognizing more than one antigen, and of binding to them to achieve a myriad of potentially useful effects. In some cases, it is simply a matter of acting on more than one target at the same time, multiplying the therapeutic efficacy of the drug or reducing the chances that a tumor develops resistance to its action. In other cases, having two different targets allows these molecules to act as a bridge between the immune system and the tumor cells: by binding to an antigen present on the immune cells they are able to activate them and ferry them towards their second target, an antigen time on the tumor cell. A form of immunotherapy, therefore, extremely selective and with a high therapeutic potential, which for many experts could have a revolutionary impact in oncology equal to what the now more traditional monoclonal antibodies had in their time.

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The latest news

The first bispecific antibody entered the European market in 2017, and to date there are seven molecules of this type approved by the EMA or the American FDA. The latest addition to the list was Glofitamab, a bispecific monoclonal targeted for the treatment of diffuse large B-cell lymphoma, which works by binding to T lymphocytes and activating their action against the runaway B lymphocytes that cause the disease. In recent weeks, the drug has received FDA approval for third-line treatment, i.e. in patients with a disease relapse who have already undergone, unsuccessfully, two other systemic therapeutic regimens. The approval, which came with an accelerated procedure, is based on the results of a phase 1-2 clinical trial, which tested the drug on 132 patients obtaining an objective response rate (the percentage of patients in which the drug induces at least one significant reduction of tumor lesions) of 56%, a 43% of patients in which the disease was completely cleared, and a mean duration of response to the drug of 18.4 months.

Fixed duration of therapy

In addition to targeting a disease for which there are currently not many therapeutic alternatives, glofitamab is the first bispecific antibody approved for large B-cell lymphoma with a fixed duration of treatment, averaging eight and a half months, an important advantage for patients, who do not have to undergo continuous administrations as before until the progression of the neoplasm. The limit highlighted by the trial is instead that of the drug's toxicity, which occurs in the most dangerous cases in the form of cytokine release syndrome, a potentially lethal disorder that can induce that storm of cytokines that we have come to know during the pandemic , as a more serious side effect of Covid. Although the therapeutic regimen tested includes a pre-treatment course with another monoclonal aimed at reducing the excessive activation of T lymphocytes, more than 60% of patients experienced a cytokine release syndrome, of which 4% with severe symptoms .

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