Antibody-drug conjugates (ADCs) are targeted cancer therapies that combine monoclonal antibodies with cytotoxic payloads via chemical linkers. These therapies have been approved for the treatment of various cancers and are currently undergoing extensive clinical development for new structures. Brain cancer, particularly malignant types such as glioblastoma, is one of the most aggressive and recurrent forms of cancer. These cancers show significant resistance to conventional treatments such as radiotherapy and chemotherapy, making new therapeutic approaches urgently needed. ADCs' unique mechanism allows them to efficiently target tumor cells while minimizing damage to surrounding healthy tissues, which enhances their potential for brain cancer treatment.

What is Brain Cancer?

Brain cancer refers to malignant tumors that originate in the brain or other nervous tissues. While relatively rare, brain cancer is highly lethal. Based on the cell type and growth location, brain cancer is typically classified into primary and secondary types. Primary and secondary brain tumors both exhibit high morbidity and mortality rates. Primary central nervous system tumors account for only 1-2% of newly diagnosed cancers, yet they lead to an average potential loss of 20 years of life, ranking first among all malignant solid tumors. Secondary brain tumors (brain metastases) occur in about 10% of cancer patients and are one of the largest challenges in oncology, commonly originating from lung cancer, breast cancer, or melanoma. There is an urgent clinical need for new treatment strategies to improve the efficacy of brain tumor therapies. However, due to the blood-brain barrier (BBB), systemic treatments often struggle to achieve effective concentrations within the central nervous system.

Fig. 1. The blood–brain barrier of brain cancer (Nat Rev Clin Oncol. 2023, 20(6): 372-389).

Types of Brain Cancer

There are primary and secondary forms of brain cancer based on cell lineage and cancer. Primary brain tumours are cells that proliferate in the brain tissue: common forms include gliomas, meningiomas, neuroblastomas and medulloblastomas. Gliomas–about 80 per cent of all brain tumours – are caused by glia, which divide into low-grade (Grade I and II) and high-grade (Grade III and IV) tumours. Extremely aggressive gliomas (including glioblastoma) are aggressive and malignant, and do not survive. Meningiomas, which grow from the meninges, tend to be harmless but they can also become malignant and, because of their geographic position, are a common source of recurrence. Though they don't grow rapidly, they're a serious danger when they're not completely removed. Neuroblastomas are very aggressive tumours that usually appear in children and adolescents, and they can also spread to the brain and other regions of the nervous system. Medulloblastomas are extremely rare, rapidly spreading malignancies, usually of the cerebellum (in children and adolescents) and they often spread quickly. Other rare brain tumours – pituitary adenomas, pineal tumours, medullary tumours – are uncommon, but they still can be devastating to patients, particularly if there are specific genetic or environmental triggers.

Immunotherapy for Brain Cancer

Due to the recurrence of brain cancer and its high resistance to conventional chemotherapy, immunotherapy has gained significant attention as a promising treatment. Immunotherapies work by activating or modulating the patient's immune system to help it identify and destroy cancer cells. The main types of immunotherapies for brain cancer include:

• Checkpoint Inhibitors: These drugs work by blocking the immune escape mechanisms of tumor cells, restoring immune system activity. They inhibit checkpoint proteins like CTLA-4, PD-1, or PD-L1, thereby enhancing immune cell attacks on tumor cells. For example, anti-PD-1 and anti-PD-L1 antibodies have shown promise in clinical trials for glioblastoma.
• Cancer Vaccines: These vaccines activate the immune system to target specific tumor antigens. They can be made from tumor-specific antigens or peptide sequences, such as dendritic cell (DC) vaccines or mRNA vaccines, which direct the immune system to recognize and eliminate tumor cells. DC vaccines for glioblastoma have shown some clinical efficacy.
• CAR-T Therapy: The CAR-T therapy is essentially genetically programming the T-cells of a patient to target cancer antigens, then kill tumour cells. For glioblastoma, CAR-T treatment primarily targets EGFRvIII-expressing (mutant) epidermal growth factor receptor cells, often those least tolerant of traditional treatment.
• Oncolytic Virus Therapy: Oncolytic viruses are designed to kill the cells of the tumor while encouraging the immune system to fight it. These viruses not only kill tumor cells directly but also disseminate tumor antigens and stimulate the immune system. Oncolytic virus therapies are shown to be very anti-tumour in glioblastoma and are in clinical trials.
• ADC Therapy: ADC therapy uses a target antibody with a powerful chemotherapy drug. This particular antibody molecule attaches to antigens on the cancer cell's surface and delivers the lethal drug directly to the tumour. The ADCs' specificity lowers the toxicity to healthy cells and increases drug uptake by cancer cells. ADC treatment looks particularly promising for the treatment of brain cancers, for which drugs won't work as effectively due to the blood-brain barrier. ADCs directed against EGFRvIII were recently shown to kill cells that harboured this antigen, a promising therapeutic potential for patients with brain cancer.

Antibody Drug Conjugate Brain Cancer

ADC are complexes that link monoclonal antibodies with cytotoxic drugs, enabling them to target specific tumor antigens and directly release toxic drugs into tumor cells. ADCs have shown great potential in cancer treatment in recent years due to their high selectivity and low toxicity. In brain cancer, ADC therapy is particularly suitable for tumor types that are difficult to surgically remove or are resistant to traditional treatments, such as high-grade gliomas.

Fig. 2. ADC in brain cancer (Nat Rev Clin Oncol. 2023, 20(6): 372-389).

ADCs can be utilised for high-frequency targeted treatment of brain cancer because the antibody in them recognises antigens on the surface of tumour cells, which enables targeted therapy within the body. This mechanism prevents damage to normal tissues and lowers systemic toxicity, and is especially promising for glioblastoma, which can't be treated with other therapies. And the biggest hurdle in treating brain cancer is the blood-brain barrier, which blocks most chemotherapeutics from getting to the brain. By molecular designing ADCs, the structure and functionality of the antibody and linker can be tailored so that the drug can work even after passing the blood-brain barrier. This is due to new technology in the delivery of drugs and structural optimisation, which has expanded the use of ADCs in brain cancer. Also, ADCs in combination with other immunotherapies like checkpoint inhibitors and CAR-T therapy are more antitumor. The co-treatment of ADCs with immunotherapies not only increases efficacy but may delay or even halt tumor growth, improving patient survival.

ADC Targets in Brain Cancer

When it comes to ADC treatment for brain cancer, targeting the right target antigens is important. EGFRvIII, IL13R2, CD133 and GD2 are some common targets. EGFRvIII, an expression- and specificity-high mutation of the epidermal growth factor receptor seen in brain tumours including glioblastoma. ADCs that are based on EGFRvIII can detect and suppress tumor cell invasion and proliferation. Moreover, since IL13R2 is abundant in the majority of glioblastomas, and scarce in brain normal tissue, it could be the most suitable target for brain cancer ADC treatment to promote tumor suppression. CD133 is another cancer stem cell marker for resistance and recurrence, and so ADCs to combat cancer stem cells have been developed that dramatically decrease tumor recurrence. ADCs can attack GD2, a ganglioside found in neuroblastoma and other malignant brain tumours, to deliver cytotoxic drugs that target cancer cells. These target antigens are good targets for the targeted treatment of brain cancer, making it possible to exploit ADC therapy. Here are the most frequently used ADC targets:

ADC Linkers in Brain Cancer

ADC linkers are a major factor in the drug development for brain cancer and how effectively and safely they treat it. The main purpose of the linker is to stick the cytotoxic drug safely to the target antibody, and to deliver the drug correctly once inside the tumor cell. ADC linkers are also targeted because of the difficulty of getting drugs through the blood-brain barrier in brain cancer therapy. There are two categories for ADC linkers: non-cleavable linkers and cleavable linkers. Non-cleavable linkers link the payload to the antibody through permanent chemical bonds, ensuring a longer life in the body and avoiding drug release too early so as to not damage healthy tissues. These linkers are especially useful in brain cancer treatment because they do not release drugs too early into the blood stream and leave drug concentrated at the tumor site. Cleavable linkers, by contrast, implant the payload inside tumor cells by cleaving them with an enzyme, and then deliver the drug to the cancer cell.

ADC Payloads in Brain Cancer

In brain cancer drug development, the ADC payload is one of its core components, determining the strength of its therapeutic effect. The payload is usually a cytotoxic drug that, once delivered into tumor cells by the targeting antibody, kills cancer cells to achieve therapeutic effect. Selecting the appropriate payload for brain cancer treatment is particularly important due to the significant challenge posed by the blood-brain barrier, which requires the payload to possess good penetration and targeting capabilities. Common payloads include microtubule inhibitors (such as mertansine, duocarmycin), DNA cross-linkers (such as carmustine), and topoisomerase inhibitors (such as irinotecan). These payloads are highly cytotoxic, capable of disrupting the microtubule structure, DNA, or RNA inside the cell after being delivered by the targeting antibody, inducing cancer cell death. For brain cancer, the lipophilicity and size of the payload are key design factors. Lipophilic payloads help drugs penetrate the blood-brain barrier more effectively, increasing drug accumulation in the brain tumor site and enhancing efficacy.

Challenges of ADC in Brain Cancer

• DAR and Uniformity

According to reports, consistency of ADC drugs is one reason why they don't deliver drugs to central nervous system (CNS) tumors. Second-generation ADCs (e.g., T-DM1) conjugate the drug-linker randomly with the monoclonal antibody, resulting in uneven DAR. By contrast, ADC drugs with novel conjugation methods have antitumor activity analogous to T-DM1 in vitro, but much better efficacy for drug delivery in the CNS and antitumour activity in vivo. ADCs that have high, non-uniform DAR accumulated in brain tumours less readily than low DAR ADCs – perhaps because high DAR ADCs are hydrophobic and have higher molecular weights, both factors that influence their aggregation in brain tumors. Yet these are from only ADCs with MMAF payload and may not be all ADCs. Notably, T-DXd, despite having a high DAR, still demonstrates significant CNS activity.

• Bystander Effect

The cytotoxic payloads could then spread bystander-effect between tumour cells in the same tumor, and may act as antitumour agents against cancer cells with low or no expression of the target antigen. ADC drugs could be regulated by their bystander effect in the nervous system. The bystander effect can also be especially relevant in brain tumours, where the blood-brain tumour barrier strictly controls drug traffic, and target antigen expression and drug concentration can be highly variable within the tumour. These can be especially acute in larger tumours. An EGFR-adjusted glioblastoma PDX model: size of tumour inversely related to drug absorption and antitumour activity of Depatux-M. Post hoc analysis of the Phase I M12-356 trial found that patients with large recurrent glioblastomas (≥25 cm³) received less overall response rate (ORR) and less median OS compared with patients with smaller tumours (<25 cm³). Logic in the engineering of ADCs to optimise bystander effect could increase their brain efficacy. These can be made with small molecules that are high-lipophilic and permeable to the membrane, or cleavable linkers that deliver neutral payloads. But a higher membrane permeability might increase drug efflux, decrease intracellular weight and reduce antitumor activity as well as off-target toxicities. These are all things that should be considered in ADC optimization.

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