Antibody-drug conjugates (ADCs) represent an innovative form of drug delivery, and there is increased interest in their use in oncology. Traditional systemic chemotherapy can expose normal, healthy cells to its cytotoxic effects. This can lead to patients experiencing numerous adverse events (AEs), which subsequently can limit the maximum tolerable dose.
ADCs link a cytotoxic agent to a monoclonal antibody (mAb) which helps target a specific antigen on a cancer cell. Once attached to the cell surface antigen via the mAb, the ADC is internalized and the “cytotoxic payload” is delivered to the cancer cell after the link is cleaved. The cytotoxic agent has direct effects on that cancer cell as well as a “bystander effect” on surrounding cells.1
In addition to being more directed toward cancer cells, ADCs also aim to reduce and overcome resistance to certain chemotherapeutic agents by utilizing novel targets. These targets include both cell surface antigens as well as antigens found within the tumor microenvironment (TME) such as seen in certain immune cells, vasculature, and the tumor stroma. Researchers are also trying to develop innovative payloads that have not been used before, such as toxins produced by certain bacteria like Pseudomonas.
Boni and colleagues recently published a review of ADCs in the 2020 American Society of Clinical Oncology (ASCO) Educational Book that includes several agents and targets in development.1 As of March 2020, there were 8 ADCs that have been approved by the US Food and Drug Administration: gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, moxetumomab pasudotox, polatuzumab vedotin, enfortumab vedotin, trastuzumab deruxtecan. The indications include solid tumors (urothelial cell cancer, HER2-positive breast cancer) and hematological malignancies (acute myeloid leukemia, Hodgkin leukemia, diffuse large B-cell lymphoma). There are up to 80 ADCs in clinical development, with close to 600 ongoing trials.2
Identification of an ideal target is one of the most challenging steps in ADC development. Ideally, a target should be exclusively expressed in tumor cells, have a rapid internalization rate, and have minimal antigen shedding within the circulation. Some researchers are working on “masked antigen sites” that are not activated until the ADC reaches the TME, which helps achieve more targeted drug delivery. The covalent link that is chosen is also crucial, which requires a delicate balance between strength of attachment to the leading mAb until the antigen is reached followed by simple uncoupling in order to exert its cytotoxic effects.
HER3 is a focus of ADC development. HER3 plays a role within breast cancer, non-small cell lung cancers (NSCLCs), and colorectal cancer (CRC). U3-1402 is an ADC in development consisting of patritumab, a fully human mAb, linked to DXd, which is a topoisomerase I inhibitor. Early studies have shown that U3-1402 has a high internalization rate, and preliminary clinical studies with optimistic findings in metastatic breast cancer and NSCLC. Future studies will focus on evaluating U3-1402 in these conditions as well as in CRC and in combination with certain EGFR and HER2-directed therapies.
Melanotransferrin (MELTF) is a cell surface protein with increased expression in several tumor types including melanoma, pancreatic, HER2-negative breast cancer, CRC, and NSCLC. MELTF may play a role in angiogenesis and cellular proliferation. SGN-CD228A is a humanized anti-CD228 mAb that targets MELTF, with the linked cytotoxic agent monomethyl auristin E (MMAE), which disrupts cellular microtubules. SGN-CD228A is currently undergoing phase 1 evaluation in multiple solid tumors including melanoma, breast cancer, NSCLC, CRC, and pancreatic cancer.
ADCs have also been a focus of targeting the immune system. CD25 (interleukin-2 receptor) is an antigen that is expressed on regulatory T cells, which play an important role in the TME and are also overexpressed in Hodgkin and non-Hodgkin lymphoma. ADCT-301 is an ADC linking an anti-CD25 mAb to a pyrolobenzodiazepine (PBD)-based toxin that is being evaluated in early-phase studies in lymphoma and solid tumors. ADCT-301 targets both lymphoma cells themselves along with the TME. Additional immune targets of ADCs include B7-H3 (CD276, an immune checkpoint) which is overexpressed in multiple solid tumors including lung, breast, renal cell, and prostate cancers. DS-7300 is a humanized anti–B7-H3 mAb linked to DXd and MGC018 is another mAb linked to a potent duocarmycin analog. A mAb targeting PD-L1 has also been linked to doxorubicin and is undergoing preclinical evaluation.