Brain Cancer Chemotherapy through a Delivery System across the Blood-Brain Barrier into the Brain Based on Receptor-Mediated Transcytosis Using Monoclonal Antibody Conjugates

Abstract

Advances in pharmacotherapy have brought extraordinary benefits to humanity. However, unmet medical needs in patients remain, particularly in the treatment of central nervous system (CNS) diseases and cancers. CNS drug delivery into the brain across the endothelium is difficult due to the blood-brain barrier (BBB), which is composed mainly of tight junctions and efflux transporters, such as multiple drug resistance 1 (MDR1) (P-glycoprotein). On the other hand, the development of anti-cancer drugs is a challenging task due to their frequent off-target side effects and the complicated mechanisms of cancer pathogenesis and progression. Brain cancer treatment options are surgery, radiation therapy, and chemotherapy. It is difficult to remove all tumor cells, even by surgical removal after a craniotomy. Accordingly, innovative brain cancer drugs are needed. Currently, antibody (Ab) drugs that show high therapeutic effects are often used clinically. Furthermore, antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan, an anti-HER2 (human epidermal receptor 2) ADC with low-molecular cancer drugs through the suitable linker, have been developed. In the case of trastuzumab deruxtecan, it is internalized into cancer cells across the membrane via receptor-mediated endocytosis. Moreover, it is reported that drug delivery into the brain across the BBB was carried out via receptor-mediated transcytosis (RMT), using anti-receptor Abs as a vector against the transferrin receptor (TfR) or insulin receptor (InsR). Thus, anti-TfR ADCs with cancer drugs are promising brain cancer agents due to their precise distribution and low side effects. In this review, I introduce the implementations and potential of brain cancer drug delivery into the brain across the BBB, based on RMT using ADCs.

Keywords: anti-TfR ADCs with cancer drugs; anti-TfR and anti-EGFR bispecific ADCs with payloads; antibody-drug conjugates; brain cancer chemotherapy; drug delivery into the brain across the BBB; drug delivery system; pH-sensitive cleavable linkers; receptor-mediated transcytosis; state-of-the-art biomedicines; transferrin receptor-mediated endocytosis.

Figure 1

The pathway of intravenously administered antibody-drug conjugates (ADCs) against receptors such as the transferrin receptor (TfR), toward exhibiting brain cancer cell cytotoxicity through receptor-medicated transcytosis (RMT) in the secretory pathway. The mAb-TfR complex was liberated under weakly acidic conditions in the endosomes. Furthermore, linked drugs acting as a payload were also liberated via the cleavage of pH-sensitive cleavable linkers under weakly acidic conditions in the endosomes. Drugs released into the brain parenchyma can be transported into cancer cells and can show anti-cancer activity. Y represents a monoclonal antibody (mAb). The blue sphere indicates a receptor that mediates transcytosis in the capillary endothelial cells at the blood-brain barrier. The red ovals represent a drug that is tethered with a mAb through a suitable linker. The dotted line indicates a linker contained in an ADC. The solid line represents the membrane.

Figure 2

Structures of low-molecular drugs that are used clinically for brain cancers.

Figure 3

The typical structure of antibody-drug conjugate (ADC).

Figure 4

The structure of trastuzumab deruxtecan (Enhertu^®), with a drug-to-antibody ratio (DAR) of 7.7.

Figure 5

The structure of idursulfase beta, composed of anti-TfR (transferrin receptor) mAb (monoclonal antibody) and iduronate-2-sulfatase.

Figure 6

The structures of anti-TfR mAbs, conjugated to active cargos.

Figure 7

The structures of anti-TfR (transferrin receptor) antibody-drug conjugate (ADC), containing cancer drugs via pH-sensitive cleavable linkers.

Figure 8

One of the structures of bispecific IgG against transferrin receptor (TfR) and vascular endothelial growth factor (VEGF).

Figure 9

The structures of low-molecular drugs that are potential vascular endothelial growth factor (VEGF) inhibitors.

Figure 10

The structure of lysine-specific demethylase-1 (KDM1A) inhibitors such as NCL-1 and NCD-38.

Figure 11

The structure of lysine-MCC-DM1.

Figure 12

The structure of anti-TfR (transferrin receptor) and anti-EGFR (epidermal growth factor receptor) bispecific ADC with low-molecular payloads.