Abstract
Solid tumors adopt multiple mechanisms to grow, evade immune responses, and to withstand therapeutic approaches. A major breakthrough in the armamentarium of anti-cancer agents has been the introduction of monoclonal antibodies (mAbs), able to inhibit aberrantly activated pathways and/or to unleash antigen (Ag)-specific immune responses. Nonetheless, mAb-mediated targeted pressure often fails due to escape mechanisms, mainly Ag loss/downregulation, ultimately providing therapy resistance. Hence, in order to target multiple Ag at the same time, and to facilitate cancer-immune cells interactions, bispecific antibodies (bsAbs) have been developed and are being tested in clinical trials, yielding variable safety/efficacy results based on target selection and their structure. While in hematologic cancers the bsAb blinatumomab recently reached the Food and Drug Administration (FDA)-approval for B Cell Acute Lymphoblastic Leukemia, bsAbs use in solid tumors faces considerable challenges, such as target Ag selection, biodistribution, and the presence of an immune-suppressive tumor microenvironment (TME). This review will focus on the state-of-the art, the design, and the exploitation of bsAbs against solid malignancies, delineating their mechanisms of action, major pitfalls, and future directions.
Highlights
Immunotherapy has recently changed both the treatment modalities as well as the prognosis across several malignancies
The combination of zanidatamab plus immunotherapy is under evaluation in a phase IB/II clinical trial in first line treatment (NCT04276493): in cohort 1, patients affected by HER2+ metastatic breast cancer (BC) will receive the drug in combination with docetaxel; in cohort 2, patients affected by HER2-positive advanced gastric/gastroesophageal junction adenocarcinoma will receive zanidatamab plus chemotherapy and tislelizumab [53]
Cells, suggesting the establishment of broad anti-tumoral immune responses [87]. Another combinatorial approach envisions the use of CART.bispecific T-cell engagers (BiTEs), in which chimeric antigen receptor (CAR)-T cells co-express and secrete functional BiTE molecules. This platform has been tested in a pre-clinical model of human glioblastoma, with T cells encoding for an anti-EGFRvIII CAR together with an anti-epidermal growth factor receptor (EGFR)-CD3 BiTE, resulting in elimination of tumors displaying heterogeneous cells (EGFRvIII positive and negative), with considerable potential advantages to EGFRvIII-specific CAR-T cell therapy alone [88]
Summary
Immunotherapy has recently changed both the treatment modalities as well as the prognosis across several malignancies Such immune-stimulating therapies entail either passive (i.e., monoclonal antibodies, adoptive cell therapies, cytokines) or active (i.e., cancer vaccines, oncolytic viruses, checkpoint blockade) approaches [1,2]. Clinical responses to immunotherapies are vastly heterogeneous, according to patient-, tumor-, or treatmentrelated characteristics. In this context, the ability of eliciting Ag-specific anti-cancer immune responses has been linked with impressive and durable responses in several malignancies. Pharmaceuticals 2021, 14, 884 this scenario, with the aim to tackle evasion mechanisms adopted by tumors upon strong therapeutic pressure, the production of bispecific antibodies (bsAbs) became a reality thanks to protein engineering advancements. We will summarize major characteristics of bsAbs underlying their activities, we will discuss the most advanced drug products tested against solid malignancies and provide an overview on the potential future advancements in the bsAb field
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