Full article: Exploration of the antibody–drug conjugate clinical landscape

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ABSTRACT

The antibody–drug conjugate (ADC) field has undergone a renaissance, with substantial recent developmental investment and subsequent drug approvals over the past 6 years. 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:

ADCs as a new class of targeted therapeutics

A new class of precision medicines, antibody–drug conjugates (ADCs), was ushered into oncology clinical practice in 2000 with the US Food and Drug Administration (FDA)’s approval of Mylotarg^TM for the treatment of acute myeloid leukemia (AML). ADC molecules marry the precision of antibody-mediated tumor antigen targeting with potent cytotoxic agents, thereby creating a targeted delivery vehicle for malignant tumors. In this manner, ADCs provide a means to reduce off-tumor toxicities by limiting payload exposure in normal tissues. While most ADC clinical candidates utilize cytotoxic chemotherapeutic payloads, recent ADC candidates have also incorporated targeted small molecules^Citation1 and immunomodulatory agents.^Citation2 In the 23 years since Mylotarg^TM’s first registration, only 12 of 267 clinically tested ADCs have made it to regulatory approval; 10 occurring in the last 6 years []. Insights into biologic engineering and utilization of less potent linker-payloads (e.g., Enhertu^TM) have re-energized the field and ushered a new wave of drug approvals.

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 Two candidates, Mylotarg^TM and Blenrep^TM, had their approvals withdrawn (red boxes) due to failure to meet requisite endpoints in post-approval trials.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.

Factors affecting activity of ADCs

ADCs offer several advantages over standard chemotherapies, notably: 1) precision delivery of cytotoxic payloads to cells expressing the selected target antigen, 2) enablement of more potent cytotoxic payload utilization than can be administered systemically, and 3) potential minimization of on target/off tumor toxicity. The promise of ADCs, when successfully designed, is the ability to broaden the therapeutic index over that of systemically administered chemotherapy. By directly delivering the cytotoxic payloads to the tumor tissue, the minimum effective dose (MED) is lowered with corresponding reduction in on target/off tumor adverse events.

Effective analysis of the clinically tested ADC molecules necessitates a fundamental understanding of the factors that modulate their biological activity. The basic cellular processes underlying ADC cytotoxic payload delivery have three key parts. First, the antibody binds to the target antigen on the surface of an antigen-positive cell. Second, the antigen-ADC complex is internalized into the target cell by receptor-mediated endocytosis. Third, the antigen-ADC complex is digested by lysosomal enzymes, releasing the cytotoxic payload that triggers cell death. As illustrated in and discussed below, the effectiveness of these basic cellular processes underlying ADC clinical activity are further modulated by various factors, notably the target antigen, functional attributes of the created antibody, conjugation chemistries, linker attributes, and payload potency and effectiveness for a chosen tumor indication.

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.

Target antigen

For an ADC to be effectively internalized within a given cell, a requisite target antigen density needs to exist to trigger efficient receptor-mediated endocytosis. A target antigen density of approximately 10,000 copies/cell or greater has been proposed as a minimum threshold for efficient biologic-mediated ADC internalization.^Citation3 Cells with target antigens expressed at lower molecular densities exhibit inefficient ADC internalization with a subsequent reduction in payload delivery. Inefficient ADC internalization can also result in ADC recycling outside of the cell prior to payload processing and release, further reducing the ADC’s cytotoxic effect.^Citation4 In addition to requisite tumor antigen densities to trigger efficient internalization, the ideal targets chosen for ADC drug development would demonstrate significantly elevated tumor antigen expression over that of normal tissues to minimize the potential for on target/off tumor toxicities. A favorable example of a target that is significantly overexpressed in tumor tissues relative to normal tissues is the HER2/neu antigen that is expressed at lower levels on a subset of normal cells, but expressed at hundreds of thousands to over a million copies on HER2+ cancer cells.^Citation5 Indeed, ADCs targeting the HER2 antigen have demonstrated robust internalization into HER2-targeted tumor cells with efficient payload delivery^{Citation6,Citation7} that has translated to clinical benefit and ultimate drug approval.^{Citation8,Citation9} In contrast, ADCs targeting tumor antigens with heterogeneous/low target antigen expression, such as the prolactin receptor with antigen densities of thousands to tens of thousands of molecules/cell,^Citation10 failed to demonstrate clinical responses at the biologic doses tested and were subsequently terminated from future clinical development.^Citation11

Antibody

Target epitope choice of a given biologic can greatly alter the effectiveness of the created ADC. Notably, biologics targeting epitopes that promote rapid receptor-mediated internalization show greater activity than biologics targeting non-internalizing epitopes.^Citation12 In addition to epitope choice, biologic affinity can also alter the effectiveness of ADC biologics. Indeed, biologics with lower affinities may demonstrate insufficient binding and/or internalization at lower target antigen densities^Citation13 and biologics with too high cellular affinities may result in reduced receptor occupancy and/or internalization.^Citation14 Biologic affinity tuning may also help mitigate on target/off tumor toxicities for antigens expressed in normal tissues of concern. Creating biologics with lower cellular affinities could help mitigate toxicity toward target positive normal cells while retaining potency against tumor cells where the given antigen is overexpressed. A preclinical example of this concept is the low affinity EGFR ADC RN765C that demonstrated robust killing of EGFR-positive cell lines/tumor models where EGFR is overexpressed with reduced toxicity against EGFR-positive normal human keratinocytes.^Citation13

Conjugation

Most ADCs use nonspecific lysine or cysteine residue-directed biologic conjugation. Both conjugation approaches have been found to generate heterogenous ADC products.^{Citation15,Citation16} In contrast, site-specific conjugation to native or engineered amino acid residues has been shown to generate more homogenous ADC drug products with improved pharmacokinetic (PK) properties and safety profiles.^{Citation17,Citation18}

Linker

Linkers can be cleavable or non-cleavable. Cleavable linkers are designed to release the payload inside the targeted cell by protonolysis, thiol reduction, proteolysis, or carbohydrate hydrolysis. In addition to cytosolic payload release, cleavable linkers have also been shown to be cleaved extracellularly due to the presence of cleaving agents in the blood and/or tumor microenvironment (TME). These linkers can be associated with both increased adverse events (due to systemic payload release)^Citation19 and increased efficacy due to noted “bystander effects” (wherein released payload can diffuse across the plasma membrane of a higher tumor antigen expressing cell to adjacent tumor cells with lower antigen expression).^Citation20 An ADC can also be created with a non-cleavable linker that only releases payload after proteolysis by lysosomal enzymes. These released payload-adducts are modified such that they do not diffuse across plasma membranes, which limits both their systemic adverse effects but also mitigates the efficacy benefit to neighboring tumor cells due to diminished bystander diffusion.^Citation21 An excellent example of this concept is the approved clinical ADC, Kadcyla^TM, that employs a non-cleavable linker, limiting its systemic toxicity as well as efficacy to bystander cells expressing lower target antigen densities. Enhertu^TM, in contrast, uses a cleavable linker, and demonstrates bystander killing and greater clinical activity in tumors with lower HER2 target expression.^Citation9 In a head-to-head clinical trial, Enhertu^TM demonstrated superior clinical activity (mPFS 28.8 months, Enhertu^TM versus 6.8 months, Kadcyla^TM) with comparable incidence of Grade 3 or higher treatment-emergent adverse events (56%, Enhertu^TM versus 52%, Kadcyla^TM) and serious treatment-emergent adverse events (25%, Enhertu^TM versus 22%, Kadcyla^TM).^Citation22 In addition to linker choice, choice of payload and presence of tumor drug efflux pumps could have also contributed to these clinical results. Linkers can also vary by their degree of hydrophilicity. Indeed, more hydrophilic linkers have been shown to increase the solubility and favorable PK properties of the ADCs, especially those that use more hydrophobic drug payloads.^Citation23

Payload

The traditional chemotherapeutic ADC payloads fall into three general classes: 1) microtubule inhibitors, 2) DNA-damaging agents, and most recently 3) topoisomerase I inhibitors. The potencies of these payload classes dictate the ADC efficacy and toxicity. Early ADC candidates utilizing low potency payloads of systemically administered chemotherapies (e.g., doxorubicin, IC₅₀ ~ 10^–Citation7 M) were ultimately abandoned due to insufficient clinical activity at administered drug exposures.^{Citation24,Citation25} As a result, the ADC field pivoted to the use of increasingly more potent cytotoxic payloads, such as the DNA damaging agents calicheamicin (IC₅₀ ~ 10⁻¹⁰ M) and pyrrolobenzodiazepines (PBDs) (IC₅₀ ~ 10⁻¹² M) and microtubule inhibitors such as monomethyl auristatin E, MMAE (IC₅₀ ~ 10⁻¹⁰ M) for follow-on drug development.^Citation26 Utilization of very potent payloads, however, limited the biologic doses that could be administered, often resulting in suboptimal payload delivery to tumors with lower target antigen densities.^{Citation27–31} In addition to payload choice, payload ADC effectiveness is also influenced by the 1) number of payload molecules per ADC (drug–antibody ratio, DAR), 2) presence of multi-drug resistance (MDR) efflux pumps in tumors that can expel select payloads, 3) potential bystander functionality of the payload once released, and 4) payload clearance. Bystander functionality is determined by whether the free payload, once released, can diffuse across cellular membranes to trigger a cytotoxic effect. The net charge on the released payload has been found to influence this functionality. For example, released neutral lipophilic MMAE payloads can diffuse across cell membranes to produce a bystander effect, whereas charged MMAF (monomethyl auristatin F) molecules cannot.^Citation32

Payload hydrophobicity has been found to modulate the clearance of the payload. More hydrophobic payloads tend to exhibit more rapid clearance, altering the on-target efficacy and off-target toxicity of a given ADC.^Citation23 In vivo payload metabolism can also modulate ADC safety and efficacy. For example, the SN-38 payload becomes inactivated in the liver with the opening of the lactone ring, dampening its cytotoxic functionality.^Citation33 Finally, clinical success of the ADC depends upon appropriate matching of the payload class to the desired indication as described below.

Indication

The clinical effectiveness of an ADC also depends on the nature of the tumor being targeted. In general, tumors with heterogeneous and/or low target antigen levels are difficult targets for ADCs. Engineering ADCs with bystander activity may in part overcome this challenge as was demonstrated with Enhertu^TM’s recent approval in HER2 low breast cancer.^Citation9 Tumors with robust expression of multidrug efflux pumps, which expel payloads from tumors, also present challenges for certain classes of ADC payloads. Indeed, ADC resistance in these high efflux tumors can be circumvented with different payload utilization.^{Citation34,Citation35}

In summary, matching the appropriate tumor antigen to selected ADC linker-payloads for a given cancer indication is critical for development of successful ADC therapeutics.

Analysis of oncology ADCs that have entered clinical trials

Here, we review ADCs registered for at least one human clinical trial for an oncology indication by January 1, 2023, that were included in the Beacon Targeted Therapies Clinical Trials and Pipeline Database (beacon-intelligence.com). We included ADCs that possessed the following two elements: 1) a targeting moiety comprising an antibody, antibody-fusion, or antibody fragment and 2) a payload. The utilized payload is one from either a conventional chemotherapeutic class or a targeted small molecule and/or immune-modulator. Radioisotope ADCs were excluded from this analysis.

In the 26 years since the first ADC clinical trial in 1997, 266 additional ADCs have been tested in over 1200 clinical trials. During this period, 54 ADC programs have been formally discontinued and 38 ADCs have been removed from company pipelines. ADCs covered in this review are classified as 1) Approved (by FDA), 2) Active (not approved by FDA but currently in ≥1 clinical trial), and 3) Discontinued (no longer listed in the company’s clinical pipeline, irrespective of an announcement of discontinuation) []. It should be noted that all Approved ADCs are also currently active in several clinical trials though they are not included in the ‘Active’ category for the purpose of this review (to eliminate double-counting). Additionally, all of the FDA Approved ADCs are approved in other countries in addition to the United States.

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.

Summary of tumor antigens targeted by clinically tested ADCs

The tumor antigen targets and the most advanced stage of clinical testing are illustrated in . To date, a total of 106 tumor antigens have been targeted by ADC drug candidates. The 11 approved ADCs target 10 unique cancer antigens: 5 ADCs target hematologic cancer antigens and 6 target solid tumors [, ]. Select antigens are the targets of multiple ADCs, including HER2 (41 candidates), Trop-2 (14), CLDN18.2 (11), and EGFR (11). Fewer than 2% of the clinical ADC candidates target more than 1 epitope of selected cancer antigen(s): four bispecific and one biparatopic ADCs are included in this review.

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.

Table 1. Attributes of FDA Approved ADCs and Approval Indications.

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Summary of linkers utilized by clinically tested ADCs

Linkers fall into two major classes: cleavable and non-cleavable []. Of the clinical ADCs, 54% use cleavable linkers, which represent the most utilized linker class. Ten of 11 clinically approved ADCs use protease-cleavable linkers. Of the clinically tested ADCs, 16% use non-cleavable linkers, including the clinically active ADC Blenrep^TM. Only one approved ADC, Kadcyla^TM, uses a non-cleavable linker. Linker class was not disclosed for 31% of the clinically tested ADCs.

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., β-Glucuronide.

Summary of payloads utilized by clinically tested ADCs

Payloads fall into four major classes: 1) microtubule inhibitors, 2) DNA-damaging agents, 3) topoisomerase I inhibitors, and 4) targeted small molecules (SM) []. Microtubule disrupting agents represent the largest payload class (57%) that have undergone clinical testing. Seven of the 11 approved ADCs use microtubule inhibitor payloads. DNA damaging agents comprise the next largest payload class (17%) of ADCs. In this subgroup, 26 of 45 molecules use highly potent PBD payloads, only one of which was granted FDA approval. Two additional approved ADCs employ the DNA damaging class by utilizing the calicheamicin payload. Topoisomerase I inhibitors are included in 7% of clinically tested ADCs. Of the 11 approved ADCs, two use topoisomerase I inhibitor payloads. In addition to these traditional chemotherapeutic payload classes, roughly 5% of ADCs incorporate targeted small molecules such as Bcl-xL inhibitors, as well as immunomodulatory agents such as TLR and STING agonists. No candidate in this non-chemotherapeutic payload class has yet been granted FDA approval. Payloads for 15% of the clinically tested ADCs are not disclosed.

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.

Summary of conjugation methods utilized by clinically tested ADCs

Of the 267 clinical ADCs, 111 candidates utilized nonspecific amino acid conjugation, 72 candidates utilized site-specific conjugation, and 84 candidates did not disclose the conjugation method for ADC creation. Of the ADC candidates that utilized site-specific ADC conjugation, 2 Approved (Enhertu^TM and Trodelvy^TM), 50 Active, and 26 Discontinued ADCs underwent clinical testing. With the exception of the DAR = 8 ADCs (e.g., Enhertu^TM and Trodelvy^TM) that utilize all natural disulfide bonds for conjugation, the remaining ADCs utilized site-specific conjugation methods that either retain the four inter-chain disulfide bonds or replace these with chemical covalent bonds (e.g., disulfide rebridging).^Citation36

Approved ADCs

The FDA has approved 12 ADCs to date [, and ], 6 each for hematologic and solid tumor malignancies, respectively [, ]. Accelerated conditional approvals were granted to 9 of the 12 approved ADCs. Approvals were withdrawn for 2 (Mylotarg^TM and Blenrep^TM) of the 12 ADCs []. Mylotarg^TM was withdrawn in 2010 due to safety versus clinical benefit concerns but was re-approved in 2017 at a lower dose in combination with chemotherapy.^Citation37 Blenrep^TM was withdrawn in 2022 when the confirmatory trial did not meet the requisite post-approval efficacy endpoints.^Citation38

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.

Of the 11 currently FDA approved ADCs, 6 utilize microtubule inhibitor payloads. Three approved ADCs use DNA damaging payloads, while 2 carry payloads that inhibit topoisomerase I []. These payloads span a range of potency from the highly potent DNA damaging agent PBD (IC₅₀ ~ pM) to the lower potency topoisomerase I inhibitor SN-38 (IC₅₀ ~ nM).^Citation39 Although the sample size is small, approved ADCs used higher potency payloads when targeting hematological malignancies and lower potency payloads were used in ADCs targeting solid tumors. Higher drug exposures required for efficacy in the solid tumor setting may limit utilization of higher potency payloads with reported increased systemic toxicity at the preferred biologic dose.

Active ADCs

Of the 164 Active ADCs, ~7% are in Phase 3 clinical testing. These active late-stage ADCs target the following tumor antigens: BCMA (belantamab mafodotin), CEACAM5 (tusamitamab ravtansine), c-Met (telisotuzumab vedotin), HER2 (trastuzumab duocarmazine and trastuzumab rezetecan), HER3 (patritumab deruxtecan), NaPi-2b (upifitamab rilsodotin), and Trop-2 (datopotamab deruxtecan and SKB264).

Microtubule inhibitor payloads are utilized by most ADCs in the active ADC group (~54%), followed by DNA damaging (10%), and topoisomerase I inhibitor (~9%) payloads. Payloads of ~22% of Active ADCs are undisclosed []. Among microtubule inhibitor ADCs, auristatins are most abundant, followed by maytansines. In the DNA damaging payload class, PBDs comprise ~50% of the clinically active ADCs.

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.

Of the cancer antigens targeted by the clinically active ADCs, ~16% target hematologic tumor antigens, ~80% target solid tumor antigens, and ~4% are directed against a cancer antigen that is expressed in both hematologic and solid tumor malignancies. The most frequently targeted tumor antigens in the Active ADC category include HER2 (32 candidates), Trop-2 (11), CLDN18.2 (11), and EGFR (8).

Discontinued ADCs

Discontinuation of ADCs can be ascribed to one or more of the following three reasons: 1) insufficient therapeutic benefit due to intolerable toxicity, 2) therapeutic benefit not superior to current standard of care due to insufficient efficacy, and/or 3) business/commercial considerations. Details of all the discontinued ADCs are shown in .

Table 2. Discontinued ADCs by Payload Class and Malignancy Setting.

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Potential factors contributing to insufficient therapeutic benefit due to intolerable toxicity include 1) on target/off tumor toxicity, 2) utilization of very high potency payloads for antigens requiring higher biologic exposures, 3) labile linkers leading to off-tumor release of payload, 4) off-target toxicity, possibly due to pinocytosis of the ADC, and 5) metabolic conversion of the payload to a more toxic metabolite. Approximately 29% of the clinically tested ADCs cited intolerable toxicity as a reason for program termination. Examples of ADCs with intolerable toxicity that could in part be due to on target/off tumor toxicity include bivatuzumab mertansine (CD44v6, expressed in skin keratinocytes) – fatal desquamation,^Citation74 MEDI-547 (EphA2) – bleeding and coagulation adverse effects (adverse events not typically associated with the MMAE payload),^Citation66 and PF-06664178 – rash adverse events (Trop-2, expressed on the surface of normal epithelial including skin).^Citation71 For the latter example of PF-06664178, an additional potential contributing factor to the severity of skin toxicity noted is the potent auristatin payload pairing with this Trop-2-targeting ADC. Indeed, the severity of the skin toxicity of PF-06664178 is markedly different from the approved Trop-2-targeting ADC, Trodelvy^TM, which uses a lower potency topoisomerase I inhibitor payload.^Citation111 Additionally, skin toxicity has also been noted for another auristatin ADC, Padcev^TM, targeting Nectin-4 (also expressed in the skin).^Citation112

Microtubule inhibitor payload ADCs account for 63% of discontinued candidates, followed by DNA damaging (~27%) payloads. Topoisomerase I inhibitors, targeted small molecules, and undisclosed payloads combined comprise 10% of discontinued ADCs []. Utilization of high potency payloads for antigens requiring higher biologic exposures was a likely contributing factor to the intolerable toxicity of several discontinued ADC candidates. The payload choice of biparatopic tetravalent HER2-directed ADC MEDI4276 could have contributed to the intolerable toxicity at doses >0.3 mg/kg.^Citation91 Indeed, the chosen tubulysin analogue payload (IC50 ~ low pM) is in the potency range of PBD payloads.^Citation113 None of the clinically approved ADCs for solid tumors (including 2 ADCs targeting the HER2 antigen) use payloads in this potency range – the most active of which is an ADC employing the less potent payload (Enhertu^TM).^Citation22 Safety was noted as the reason for termination HER2 for the PBD-conjugated ADCs ADCT-502^Citation25 and DHES0815A.^{Citation93,Citation94}

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.

ADCs targeting six tumor antigens of the approved ADCs (CD19, CD22, CD33, CD79b, HER2, and Trop-2) have also been discontinued, some due to intolerable toxicity. Trodelvy^TM, the approved Trop-2 ADC using the lower potency topoisomerase I payload SN-38 (IC₅₀ ~ nM), requires high biologic exposures to achieve the desired efficacy benefit (10 mg/kg on days 1 and 8 of a 21-day treatment cycle). Two ADCs targeting Trop-2 have been discontinued, most likely due to too potent payload selection pairing with a tumor antigen target requiring higher biologic exposures. PF-06664178, which uses a highly potent auristatin analog payload (IC50~ low pM),^Citation114 generated dose-limiting toxicities without any partial and/or complete responses in patients treated with doses up to 4.8 mg/kg every 3 weeks (doses ≥3.6 mg/kg deemed intolerable due to dose-limiting toxicities of rash, mucositis, and neutropenia).^Citation71 No clinical trial data have been published surrounding the highly potent maytansine payload ADC, BAT8003, although dose-limiting toxicities are suspected.

CD79b is targeted by the approved ADC Polivy^TM. A follow-on site-specific CD79b-targeting ADC, iladatuzumab vedotin, was tested in combination with rituximab. Iladatuzumab vedotin was ultimately discontinued because no improvement in the therapeutic index (vs Polivy^TM) was noted due to ocular toxicity at higher doses.^Citation60

Three ADCs targeting CD33, the target of Mylotarg^TM, were also discontinued. AVE9633 (DM4 payload) showed no clinical activity below toxic doses;^Citation89 IMGN779 (indolino-benzodiazepine dimer payload) where efficacy was not reported;^Citation106 and vadastuximab talirine (PBD payload) that was discontinued following combination studies with hypomethylating agents citing safety concerns that included fatal infections.^Citation97 One CD33 targeting ADC with a tubulysin payload, DXC007, is currently in Phase 1 (Registration number CTR20221074), although safety and efficacy data have yet to be released.

Infusion-related adverse events were cited for the discontinuation of LOP628 (c-KIT)^Citation79 and losatuxizumab vedotin (EGFR).^Citation40 Additionally, poor tolerability and lack of objective responses of DCLL9718S (CLL-1) at doses tested did not justify its further development.^Citation99 In some discontinued ADCs, the clinical toxicity profile did not match preclinical observations, such as the CDH6 targeting ADC, HKT288, that showed neurological toxicity in patients not observed in preclinical models.^Citation84 Similarly, aprutumab ixadotin (FGFR2) had a clinical MTD below the therapeutic threshold estimated preclinically.^Citation68 These latter two examples highlight the need for better predictive models to guide ADC clinical development.

In addition to intolerable toxicity, insufficient efficacy is also a cause of ADC discontinuation. Factors contributing to insufficient efficacy include 1) low tumor target antigen densities and/or poor internalization properties of discontinued ADCs, 2) insufficient payload potency, 3) heterogenous DAR ADC products resulting in sub-optimal doses of payload, 4) off-tumor payload release and/or incomplete drug release in tumors, 5) rapid clearance of ADC due to poor PK properties, 6) failure to demonstrate efficacy superiority over standard of care, and 7) multidrug resistance mediated through elevated drug efflux transporters in tumors.

Of the discontinued ADC candidates where data is available, insufficient efficacy was a likely contributing factor in ~47% of the cases. Candidates that were reported to demonstrate insufficient efficacy to warrant further clinical testing include, but are not limited to, tamrintamab pamozirine (DPEP3),^Citation27 PF-06647263 (EFNA4),^Citation100 and PCA062 (P-Cadherin).^Citation81 It is possible that some of these ADC targets had heterogenous tumor expression and/or insufficient tumor antigen densities to induce efficient ADC internalization.

Utilization of payloads with insufficient potency, contributing to insufficient efficacy, was a possible contributing factor leading to discontinuation of the HER2-targeting immunomodulatory ADCs NJH395 and SBT6050. No objective responses were observed in 18 patients treated with NJH395 (TLR7 agonist payload).^Citation109 Likewise, only one of 14 patients achieved a partial response with SBT6050 (TLR8 agonist payload).^Citation110 For these TLR agonist ADCs, it is also possible that the lack of clinical activity is tied to suboptimal activation of an antitumor immune response. The clinical HER2 maytansinoid ADC BAT8001⁹⁰ was discontinued, possibly to advance a less potent topoisomerase I inhibitor payload ADC (BAT8010). This discontinuation/advancement decision is in line with the clinical experience of the two approved HER2 ADCs, Kadcyla^TM and Enhertu^TM, where the ADC employing the lower potency payload (Enhertu^TM) demonstrates greater clinical activity.^Citation115

ADCs with heterogenous DAR mixtures resulting in sub-optimal doses of payload was the likely cause of the lower efficacy observed with the nonspecific cysteine conjugate MUC16 ADC, sofituzumab vedotin,^Citation52 when compared to the specific cysteine (THIOMAB^TM) conjugate ADC, DMUC4064A.^Citation53 CMB-401 (MUC1) is an example of an ADC discontinued due to insufficient efficacy that may in part be due to poor linker choice leading to off-tumor payload release.^Citation102 It was suggested that the failure of this calicheamicin ADC to elicit a single partial remission was due to the utilization of the labile amid linker.^Citation102 MEDI4267 is an example of an ADC discontinued due to poor PK properties (and intolerable toxicity). It was noted that this HER2-targeted tubulysin ADC, at MTD, had a very short half-life and high clearance relative to the HER2-targeted ADC, Kadcyla^TM, at its MTD.^Citation91

Seven ADCs were discontinued due to failure to demonstrate superiority over standard chemotherapy comparator arms: rovalpituzumab tesirine (DLL3),^{Citation28,Citation29} depatuxizumab mafodotin (EGFRvIII),^{Citation64,Citation116,Citation117} AMG 595 (EGFRvIII),^Citation80 AGS16F (ENPP3),^Citation65 glembatumumab vedotin (gpNMB),^Citation46 and lifastuzumab vedotin (NaPi-2b).^Citation54 Supplementing standard chemotherapy with lorvotuzumab mertansine (CD56) increased incidence of adverse events without enhancing efficacy.^{Citation76,Citation118}

Clinical information regarding the remaining 22 of the 92 discontinued ADCs remains unpublished (AbGn-107, AGS67E, BAT8003, BIIB015, cantuzumab ravtansine, IMGN388, milatuzumab doxorubicin, laprituximab emtansine, lupartumab amadotin, MEDI2228, MEDI7247, PF-06688992, SAR428926, SBT6290, SC-005, SC-006, SGN-CD19B, SGN-CD48A, SGN-CD123A, SGN-CD352A, sirtratumab vedotin, and XMT-1592). Of these 22, companies cited portfolio prioritization/strategic considerations and lack of accrual for 48% and 2% of discontinuations, respectively, but no reason for discontinuation was given for the remaining 50%.

Implications for future ADC drug design

Development of the next generation of ADCs with a potential to improve their therapeutic index can be broken down into the three main components of the ADC (antibody, linker, payload) and the conjugation technology used to link the antibody to the payload. Also, consideration of the need to match the appropriate payload to a given tumor indication is required, while being mindful of the cancer antigen densities of the tumor targeting biologic.

Improvements to the biologic

Improvements in antibody design include binder selection and engineering to 1) select epitope(s)/affinities that promote maximal internalization, 2) optimize/lower affinity of binders for targets with higher expression on normal tissues of concern, and 3) fine tune the net charge of the ADC to mitigate target-independent toxicity.

Biologics targeting epitopes that promote rapid receptor-mediated internalization show greater activity than biologics targeting non-internalization antigen epitopes.^Citation12 Additionally, biparatopic and bispecific ADC biologics have been reported to improve ADC internalization, increasing the ADC effectiveness in tumors with lower target antigen densities.^{Citation119,Citation120} Biparatopic and bispecific ADCs currently in testing include REGN5093-M114 (c-MET, c-MET), zanidatamab zovodotin (HER2, HER2), IMGN151 (FRα FRα), BL-B01D1 (EGFR, HER3), M1231 (EGFR, MUC1), and ORM-5029 (HER2, HER3).

In addition to selecting internalizing epitopes and/or biparatope/bispecific antigen targeting, biologic affinity optimization of ADC biologics would need to be tailored for the antigen(s) of choice. Indeed, biologics with lower affinities may demonstrate insufficient binding and/or internalization at lower target antigen densities^Citation13 and biologics with too high cellular affinities may result in reduced receptor occupancy and/or internalization.^Citation14 Biologic affinity tuning may also help mitigate on target/off-tumor toxicities for antigens expressed in normal tissues of concern. Affinity de-tuning has been shown to lower target-dependent toxicity in normal tissues while maintaining activity on tumor cells with higher target antigen expression.^{Citation13,Citation121}

Finally, optimizing the net charge of an ADC has been demonstrated to mitigate target-independent toxicity. An example of this is the reduction in ocular toxicity via introduction of a single Lys to Asp mutation into the biologic of the ADC, AGS-16C3F.^Citation122 These results suggest that creating a net negative surface charge on the ADC could dampen target-independent toxicity.

Improvements to the linker

Linkers are not mere inert bridges between an antibody and a payload; they influence the stability and PK of a given ADC. Poor performance of some early ADCs, like CMB-401, has been attributed to labile linkers.^Citation102 Improvements in ADC linkers have been shown to decrease systemic payload release and improve PK properties. Along these lines, improvements in linker development could include 1) payload masking linkers, 2) hydrophilic linkers, 3) branched linkers to increase the drug load, 4) tandem cleavage linkers, and 5) dual cleavage-specific linkers.

Modifying the linker to mask the hydrophobic payload can increase the therapeutic index.^Citation123 In general, reducing hydrophobicity of an ADC improves PK and therapeutic activity,^Citation23 at least in part due to reduced micropinocytosis-induced off-target toxicity.^Citation124 Indeed, incorporating hydrophilic macrocycles in the ADC to mask the hydrophobic payloads improved the in vivo activity of Adcetris^TM-like ADCs.^Citation125

Modifying the linker to increase drug load is another strategy to increase the effectiveness of ADCs that incorporate low potency payloads. One challenge in creating traditional cytotoxic ADCs with higher DAR loads is the increased hydrophobicity of the ADC molecule due to increased numbers of hydrophobic payloads that both increase the probability of aggregation^Citation126 and hasten clearance of the ADC from the organism.^{Citation16,Citation23} Creating polymer linkers, such as Fleximer^TM linkers^Citation127 or PEG chain additions, either between the antibody and the linker or branching from a location within a traditional linker,^Citation23 can increase the drug load on the ADC molecule without the associated liabilities of biologic degradation and/or clearance. Using such methods, the DAR can be increased without increasing the overall ADC hydrophobicity. Additionally, polypeptides composed of a pseudo-repeating pattern of hydrophilic neutral or negatively charged amino acids (Ala, Gly, Pro, Ser, Thr, Glu; XTEN^TM-peptide based platform) can yield ADCs with DARs as high as 18 without compromising PK.^Citation128 Increasing linker hydrophilicity can alter the toxicity profile of the ADC by modulating the bystander effect through reduced expulsion of the payload metabolites by the MDR1 pump.^Citation129 However, this approach may not work for all ADCs.^Citation130

Lastly, modifying cleavable linkers to minimize systemic release while still maintaining tumor bystander effect could improve the therapeutic index of follow-on ADC molecules. Engineering linkers requiring successive cleavage by enzymes only found inside lysosomes could achieve this property. Such an example was described for a glucuronidase-cleavable linker that when cleaved uncovered a cathepsin cleavage site that enabled payload release – ensuring that both cleavage steps only occurred inside of lysosomes.^Citation131 Such tandem cleavage linkers were found to improve both the stability as well as tolerability of an ADC in a rat toxicity model.^Citation131

Improvements to the payload

Modifications to the payloads that could improve the therapeutic benefit of follow-on ADCs include the creation of 1) prodrug-based payloads to mitigate off-tumor toxicity, 2) creation of hydrophilic cytotoxic payloads, and 3) the creation of bifunctional payloads to increase tumor efficacy. Prodrug payloads exploit the acidic, hypoxic, hyper-sialylated, and protease-rich TME to trigger active payload release in tumors.^Citation132 Prodrugs can involve masking toxic, hydrophobic payloads such as PBDs by “capping”. The prodrug cap is designed to be cleaved by the TME enzymes, such as beta-glucuronidases, to minimize off-tumor payload release.^Citation133 The identification of additional endosomal trafficking modulators and lysosomal pathway regulators for payload release could aid in design of the next generation of prodrug payloads.^Citation134

The creation of hydrophilic cytotoxic payloads is another potential advancement to develop ADCs with elevated DARs that retain biologic integrity with good PK attributes. An example of this is the hydrophilic payload auristatin β-D-glucuronide MMAU.^Citation135 This glycoside-payload had the added benefit of being relatively inert in its unconjugated, free form. Lysosomal enzymatic processing to a deglycosylated state activates the payload’s cytotoxic and bystander activity.

The potency of an ADC can also be enhanced with the creation of dual payloads to increase tumor efficacy. Conjugation to two or more different payloads to a given biologic has been shown to have greater antitumor activity over that of a mixture of ADCs carrying the individual payloads. Preclinical studies exploring dual payload ADCs include the two different microtubule inhibitor payloads, MMAE and MMAF,^Citation136 as well as a microtubule inhibitor payload coupled with a DNA damaging agent such as MMAE and PBD,^Citation137 or MMAF and PNU-159682.^Citation138 All of these dual payload ADCs have been shown to increase the antitumor activity over that of a mixture of mono payload ADCs. Additionally, tolerability of these dual payload ADCs in healthy mice was found to be similar to the mono payload ADCs as measured by body weight loss and liver clinical chemistries.^Citation139

Improvements in payload conjugation

Site-specific attachment of payload yields ADC preparations with controlled and defined DAR. The first method to produce such ADCs via cysteine amino acid engineering gave homogeneous preparations demonstrating superior preclinical PK properties and safety profiles compared to randomly conjugated ADCs.^Citation18 These findings triggered enthusiasm in the field and led to the development of additional methods for site-specific conjugation. To date, site-selective conjugation methods fall into eight categories: cysteine engineering, non-natural amino acid engineering, conjugation to native cysteines, peptide tags, glycan modification, enzymatic modification, disulfide rebridging, and conjugation to native lysines.^Citation140 No method used to date for site-specific conjugation has been shown to have a direct effect on FcRn recycling that can alter ADC PK, efficacy, and safety.

Linker-payload conjugation via non-natural amino acid methods is currently being explored. However, it has been noted that the position of non-natural amino acid conjugation for linker-payload attachment caused a marked effect on tumor killing, although the stability and PK were equivalent.^Citation141

Examples of site-specific conjugation using peptide tag technology are the SMARTag^TM and Glutamine Tag. SMARTag^TM achieves site-specific conjugation with the use of an aldehyde tag attaching the linker-payload to formylglycine.^Citation142 Glutamine Tag technology utilizes transglutaminase to attach the linker-payload.^Citation143 Both technologies were shown to improve PK and efficacy.^{Citation142,Citation143}

GlycoConnect^TM is an example of a site-specific glycan modification conjugation method. Here, site-specific conjugation is achieved with attachment of the linker-payload following glycan remodeling of the antibody at the Asparagine-297 site.^Citation144 However, since Asparagine-297 glycans are important for antibody Fcγ-receptor effector functions, this method needs to be balanced against the loss of Fc effector function that could otherwise provide an efficacy benefit to the developed ADC.^Citation145

A notable advance in site-specific technology is the AJICAP^TM method that utilizes native lysines for site-specific linker-payload attachment. This method does not require antibody engineering or enzymatic reactions. ADCs so produced were shown to have an improved therapeutic index in preclinical models.^Citation17

Clinically, the site-specific ADC DMUC4064A (MUC16) could be administered at higher biologic doses with higher overall response rates^Citation53 than the nonspecific, cysteine-conjugated counterpart sofituzumab vedotin (MUC16).^Citation52 While promising, site-specific payload conjugation has not always resulted in therapeutic improvement. For example, the site-specific conjugated ADCs iladatuzumab vedotin (CD79b) and SC-002 (DLL3) did not demonstrate an improvement in clinical responses/therapeutic index over that of the nonspecific cysteine-conjugated ADCs Polivy^TMCitation60 and rovalpituzumab tesirine.^{Citation29,Citation92}

Concluding remarks

Of the 267 ADCs tested for oncology indications, 11 have gained FDA approval; 92 have been discontinued. Analyses of the limitations associated with the discontinued drug candidates can help inform the design and selection of the next series of molecules. Importantly, new biologic engineering modifications have been shown preclinically to improve the therapeutic index. Taking an integrated, multifactorial approach of careful target selection with simultaneous optimization of the antibody, linker, and payload – matched to the indications of interest – will hopefully usher in the next wave of new ADC approvals.

Abbreviations

ADC	=	Antibody-Drug Conjugate
ALA	=	Alanine
AML	=	Acute Myeloid Leukemia
Asp	=	Aspartic acid
DAR	=	Drug-to-Antibody Ratio
FcRn	=	neonatal Fc receptor
FDA	=	Food and Drug Administration
Glu	=	Glutamic acid
Gly	=	Glycine
IC₅₀	=	half-maximal inhibitory concentration
Lys	=	lysine
M	=	Molar
MDR	=	Multi-Drug Resistance
MED	=	minimum effective dose
mg/kg	=	milligrams per kilogram
MMAE	=	Monomethyl auristatin E
MMAF	=	Monomethyl auristatin F
mPFS	=	Medium Progression Free Survival
MTD	=	Maximum Tolerated Dose
nM	=	Nanomolar
PBD	=	Pyrrolobenzodiazepine
PK	=	Pharmacokinetic
pM	=	Picomolar
Pro	=	Proline
Ser	=	Serine
SM	=	Targeted Small Molecules
STING	=	Stimulator of Interferon Genes
Thr	=	Threonine
TLR	=	Toll-Like Receptor
TME	=	Tumor Microenvironment
US	=	United States

Acknowledgments

The authors wish to thank Beacon Intelligence for providing access to the Beacon Targeted Therapies Clinical Trials and Pipeline Database. The authors would also like to thank Allison Bruce for technical assistance with figure generation.

Disclosure statement

All authors are employees of Aarvik Therapeutics, Inc. and may have stock and/or stock options or interests in Aarvik Therapeutics, Inc.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

No funding was associated with the work of this article.

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Exploration of the antibody–drug conjugate clinical landscape

ABSTRACT