Nanobody-based CAR-T cells for cancer immunotherapy

Abstract

Chimeric antigen receptor T-cell (CAR-T) therapy is the result of combining genetic engineering-based cancer immunotherapy with adoptive cell therapy (ACT). CAR-T therapy has been successful in treating various types of hematological cancers. CARs are receptors made of an extracellular domain, a membrane-spanning domain, and an intracellular domain. The extracellular domain of CARs harbors an antigen-targeting domain responsible for recognizing and binding cell surface-expressed target antigens. Conventionally, the single-chain fragment variable (scFv) of a monoclonal antibody (mAb) is used as the antigen-targeting domain of CARs. However, of late, researchers have exploited nanobodies for this aim based on numerous rationales including the small size of nanobodies, their stability, specificity, and high affinity, and their easy and feasible development process. Many findings have confirmed that nanobody-based CAR-Ts can be as functional as scFv-based CAR-Ts in preclinical and clinical settings. In this review, we discuss the advantages and disadvantages of scFvs and nanobodies in regards to their application as the targeting domain of CARs. Ultimately, we discuss various CAR target antigens which have been targeted using nanobody-based CAR-T cells for the treatment of different types of malignancies.

The journey of CAR-T therapy in hematological malignancies

“…Therefore, CAR-T therapy can enable access to a large subset of patients. Additionally, single variable domain on a heavy chain (VHH), also called nanobodies, have also been employed as the targeting domain of CARs [ 9 ]. VHH are derived from the variable domain of heavy chain-only antibodies (HcAbs), produced by the Camelidae family and sharks naturally [ 10 , 11 ].…”

Immunovirotherapy: The role of antibody based therapeutics combination with oncolytic viruses

“…As a consequence, CAR-T cells do not exhibit profound anti-tumor effects in solid tumors. The use of VHH-based CAR-T cells (Nanobody CAR-T cells) may could resolve the abovementioned problems ( 212 , 213 ). There are different antigens that are targeted through Nanobody-based CAR-T cells, such as vascular endothelial growth factor receptor 2 (VEGFR2) ( 214 ), human epidermal growth factor receptor 2 (HER2) ( 215 ), tumor-associated glycoprotein 72 (TAG‐;72) ( 216 ), prostate-specific membrane antigen (PSMA) ( 217 – 219 ), glypican 2 (GPC2), epidermal growth factor receptor (EGFR), B‐;cell maturation antigen (BCMA), PD‐;L1, and EIIIB ( 212 , 220 ).…”

“…The use of VHH-based CAR-T cells (Nanobody CAR-T cells) may could resolve the abovementioned problems ( 212 , 213 ). There are different antigens that are targeted through Nanobody-based CAR-T cells, such as vascular endothelial growth factor receptor 2 (VEGFR2) ( 214 ), human epidermal growth factor receptor 2 (HER2) ( 215 ), tumor-associated glycoprotein 72 (TAG‐;72) ( 216 ), prostate-specific membrane antigen (PSMA) ( 217 – 219 ), glypican 2 (GPC2), epidermal growth factor receptor (EGFR), B‐;cell maturation antigen (BCMA), PD‐;L1, and EIIIB ( 212 , 220 ). It has been shown that the combination of CAR-T cells (scFv or VHH-based) with virotherapy can help CAR-T cells overcome their challenges in combat against solid tumors (such as immunosuppressive TME and heterogeneity of the antigens) and increase the immune response dramatically.…”

Nanobodies; new molecular instruments with special specifications for targeting, diagnosis and treatment of triple-negative breast cancer

“…Moreover, these nanobodies are able to diagnose mysterious epitopes and haptens that are not available to conventional antibodies [ 5 ]. Additionally, VHHs are suitable for use in treatment since they have more than 80% similarity to human VHs [ 12 ]. VHHs can be linked (fusion nanobodies) with enzymes, substrates, toxins, radioactive materials, and other biologically active substances to achieve specific functional effects [ 1 ].…”