Exploration of the antibody-drug conjugate clinical landscape

Abstract

The antibody-drug conjugate (ADC) field has undergone a renaissance, with substantial recent developmental investment and subsequent drug approvals over the past 6 y. In November 2022, Elahere^TM became the latest ADC to be approved by the US Food and Drug Administration (FDA). To date, over 260 ADCs have been tested in the clinic against various oncology indications. Here, we review the clinical landscape of ADCs that are currently FDA approved (11), agents currently in clinical trials but not yet approved (164), and candidates discontinued following clinical testing (92). These clinically tested ADCs are further analyzed by their targeting tumor antigen(s), linker, payload choices, and highest clinical stage achieved, highlighting limitations associated with the discontinued drug candidates. Lastly, we discuss biologic engineering modifications preclinically demonstrated to improve the therapeutic index that if incorporated may increase the proportion of molecules that successfully transition to regulatory approval.

Keywords: ADC; Antibody–drug conjugate; clinical trials; drug-to-antibody ratio; linker; payload; site-directed conjugation.

Figure 1.

Timeline of FDA Approvals. To date, 12 ADCs have been granted FDA approval (green boxes). Two candidates, Mylotarg^TM and Blenrep^TM, had their approvals withdrawn (red boxes) due to failure to meet requisite endpoints in post-approval trials. Mylotarg^TM was subsequently re-approved at a lower dose in combination with chemotherapy. Eleven ADC therapeutics are currently FDA approved.

Figure 2.

Factors Governing ADC Activity. Grey arrows indicate the path of an ADC into a cell. The antibody binds to the target antigen on the surface of the cell, the antigen-ADC complex is internalized by endocytosis, and the antigen-ADC complex is either recycled back to the cell surface, or transitions to the lysosomal compartment. Lysosomal processing releases the cytotoxic payload (red dots) ultimately triggering cell death. Factors governing this process include the target antigen, the antibody, the conjugation methodology to attach the payload to the biologic, the linker, the payload, and the selected tumor indication.

Figure 3.

Clinically Tested ADCs. This bar graph captures the 267 ADC that have undergone clinical testing of which: 11 are FDA Approved (green sector), 164 are in Active clinical testing (blue sectors), and 92 have been Discontinued (red sector). Additionally, for the Active ADCs, they have been broken down to highlight their highest development stage (Phase 1-Phase 4, P1-P4). The one candidate in this class listed in Phase 4 (P4), disitamab vedotin, has been approved in China and is not yet approved by the FDA.

Figure 4.

Antigen Targets of the Clinically Tested ADCs. Of the 267 clinically tested ADCs, 260 have known antigens (7 are undisclosed). Numbers of ADCs targeting a given tumor antigen in various stages of clinical testing (Phase 1-Phase 4, P1-P4) are shown in the categories of FDA Approved ADCs (green sectors, green text), Active ADCs (blue sectors, blue text), and Discontinued ADCs (red sectors, red text). Dual antigen targeting ADCs are shown in italics. The Phase 4 HER2 candidate shown in purple text is disitamab vedotin, that has been approved in China and is not yet approved by the FDA.

Figure 5.

Approved ADCs Classified by Payload Class and Malignancy Setting. Approved ADC drug name and payload are provided. ADCs are listed from top to bottom based upon the potency of the payload utilized with PBD payloads being the most potent and SN-38 payloads the least potent.

Figure 6.

Linkers Used in Clinically Tested ADCs. Numbers of ADCs utilizing different linker classes are shown in the outer ring for the FDA-approved ADCs (green), active ADCs (blue), and discontinued ADCs (red). FDA approved ADCs are shown alongside their respective linkers. Gluc., α-Glucuronide.

Figure 7.

Payloads Used in Clinically Tested ADCs. Numbers of ADCs corresponding to the type of payload are shown are shown in the outer ring for the FDA-approved ADCs (green), active ADCs (blue), and discontinued ADCs (red) sectors. Topo-I, Topoisomerase I Inhibitor; SM, targeted small molecules; PBD, pyrrolobenzodiazepine; Cal., calicheamicin.

Figure 8.

FDA Approved ADCs Classified by Payload Class. ADC drug name, target antigen, and names and chemical structures of payloads are shown. Arrows mark the point of attachment of payload to the antibody. Topo-I, Topoisomerase I Inhibitor; PBD, pyrrolobenzodiazepine.

Figure 9.

Active ADCs Classified by Payload Class. Of the active ADCs in clinical testing, the majority utilize microtubule inhibitor payloads, followed by DNA Damaging Agents, Topoisomerase I Inhibitors (Topo-I), and targeted small molecules (SM). ~22% of active ADCs have not disclosed the payload utilized (Undisclosed). PBD, pyrrolobenzodiazepine; Cal., calicheamicin.

Figure 10.

Discontinued ADCs Classified by Payload Class. The major payload classes utilized in the discontinued ADCs are the microtubule inhibitors and DNA Damaging Agents. Topoisomerase I Inhibitors (Topo-1), targeted small molecules (SM), and undisclosed candidates combined make up ~9% of the discontinued ADCs. PBD, pyrrolobenzodiazepine; Cal., calicheamicin.