ADC has established a solid position in the oncology pharmacopoeia. Over 1,500 clinical trials of ADCs are listed on clinicaltrials.gov, and an increasing number of drugs are entering clinical trials. It can be anticipated that the approved indications for ADCs will diversify significantly, as will their applications in various diseases.
Currently approved ADCs, nearly half of which are used for hematologic malignancies. The challenges in developing ADCs for solid tumors may be due to specific features, including poor penetration, intrinsic resistance to cytotoxic drugs, and reduced mitotic fraction. Enhanced tumor penetration may improve ADC activity in solid tumor indications by using smaller formats or tumor-activated probodies. Several promising targets are currently being evaluated in clinical trials for solid tumors, such as ROR1, HER3, CEACAM5, MET, and NaPi2b, and a large number of tumor-associated antigens are being explored as potential targets for ADC-mediated drug delivery.
The expected developments in ADCs will include new target antigens, effective payloads with novel mechanisms of action, new linker technologies that provide better therapeutic indices, and new antibody and carrier formats.
Inducing immunogenic cell death
Increasing research focuses on the immune-stimulatory properties of ADCs. In addition to binding immune activators, like in immune-activating antibody-drug conjugates (iADCs), ADCs can also cause immunogenic cell death (ICD), which boosts the immune system’s ability to fight tumors. The induction of ICD by ADCs may be a reason for their effective combination with immune checkpoint inhibitors, especially in immunologically rich diseases like Hodgkin’s lymphoma. Belantamab mafodotin induces ICD in vivo and activates dendritic cells in immune-active mouse models. ADCs based on anthracycline drugs targeting HER2 also induce ICD and immunogenic memory. The ability of ADC payloads to induce ICD may vary, and further research will help determine their potential as immune activators.
Targeting extracellular antigens
The initial paradigm of anticancer ADCs was based on the intracellular release of cytotoxic payloads, relying on internalization. However, a third alternative is being explored using non-internalizing antibodies targeting components of the tumor microenvironment. For example, PNU conjugated antibodies targeting the tenascin C splice isoforms induce complete remission in preclinical models. Galectin-3-binding protein (LGALS3BP), secreted preferentially by tumor cells, has been explored as an extracellular ADC target. Other potential extracellular targets for ADCs can be identified through high-throughput computational methods. While the mechanisms of action for these formulations are highly novel, they face specific obstacles, including the relative expression of the target antigen in normal tissue versus tumor tissue, sufficient payload release in the environment, and effective penetration of the payload in tumor cells. However, explicitly targeting extracellular targets with ADCs is built on the concept that the extracellular release of diffusible bystander payloads may be an underappreciated component of the mechanisms by which many ADCs target solid tumors.
Overcoming the immune-suppressive tumor microenvironment
A third approach, in addition to targeting tumor cells themselves and extracellular antigens, is the depletion of cell populations that impact therapy. Studies by Saha et al. demonstrate successful myeloablation with anti-CD45 ADCs in mice receiving allogeneic hematopoietic stem cell transplantation, indicating the potential to spare patients from whole-body irradiation or exposure to potent alkylating agents. Recently, in Phase I/II studies, a myeloablative CD117 calicheamicin ADC showed good tolerability. As our understanding of the role of immune-suppressive cells.