[Antibody drug conjugates (ADC) and bispecific antibodies in oncology - report of the 2022 Saint Louis day]. / Anticorps monoclonaux conjugués et bispécifiques en cancérologie ­ compte rendu de la Journée de Saint Louis 2022.

Antibody Drug Conjugates (ADC) and bispecific antibodies are booming and were the subject of the scientific event proposed by the French Society of Oncological Pharmacy, October 13, 2022. An ADC is composed of the antibody targeting a receptor expressed on the tumor cell, the spacer making it possible to attach the cytotoxic to the antibody and to control its distribution in the body, and the cytotoxic. Therapeutic antibodies, monoclonal and conjugated, have particular pharmacokinetics. Unlike monoclonal antibodies for which the standard dose is most often fixed, this is expressed in mg/m2 (or mg/kg) and capped at 2m2 (or 100kg) for conjugates. The linked cytotoxics are powerful cytotoxics: mitotic spindle poisons (emtansine, monomethyl auristatin E or vedotin), topoisomerase I inhibitors (deruxtecan, SN 38) or antibiotics (ozogamicin). In senology, trastuzumab deruxtecan (anti-HER2) and sacituzumab govitecan (anti-Trop 2) are now modifying treatment standards for patients with metastatic breast cancer, respectively HER2 3X or HER2 low and triple negative. In metastatic bladder cancer, enfortumab vedotin (anti-nectin 4) is positioned as the 2nd line of treatment. Bispecific antibodies, on the other hand, are able to target two epitopes, an antigen specific to a tumor cell and one to an immune cell, allowing a bridge between the killer immune cells and the tumor cells. For lymphoma proliferation, many bispecific antibodies are in development. The most advanced are glofitamab, epcoritamab and mosunetuzumab, which target the CD20 of B lymphocytes and the CD3 of T lymphocytes. Bispecific antibodies are also emerging in the treatment of myeloma with teclistamab and elranatamab (anti-CD3 and anti-BCMA) or talquetamab (anti-GPRC5D and anti-CD3). Conjugated antibodies, and more recently bispecific antibodies, are potential game changers in cancer treatment and researchs are needed to improve their efficacy and safety.

[Bispecific antibodies: An old story with a bright future with CAR-T cells!] / Les anticorps bispécifiques : une vieille histoire pleine d'avenir avec les CAR-T !

CAR-T cells originate from two different approaches, cellular immunotherapy based on tumor immunosurveillance by T lymphocytes, combined with molecular engineering of bispecific antibodies and antibody fragments. The latter makes it possible to retarget immune effector cytotoxic cells (such as NK cells and T lymphocytes) to tumor cells through the binding to tumor-associated antigens. We present herein the history of bispecific antibodies, highlighting how such antibodies played a major role in CAR-T cell development. We will first evoke how antibody engineering led to the construction of various bispecific formats, in particular using the single chain Fv fragment (scFv) which has been used as the initial building block to generate chimeric bi-, tri- or multifunctional molecules. We will also describe how bispecific antibodies, either full IgG or as scFv or F(ab')2 format, directed against Fcγ receptors or CD3ɛ and against tumor-associated antigens, induce a potent anti-tumor cytotoxicity following the recruitment and activation of immune effector cells, including CD3+ T lymphocytes. These anti-tumor effects have been translated into the clinics, especially to treat malignant hemopathies. At last, recently generated bispecific CAR-T cells suggest that the embrace between cell therapy and bispecific antibodies is not over and that we are yet to witness further discoveries enabling these cells to be even more efficient.