The Highs, Lows, and Resurgence of Antibody-drug Conjugates

Abstract
Antibody-drug conjugates (ADCs) offer a way to deliver a cytotoxic or an immuno-stimulatory payload directly to tumors to maximize the anti-tumor efficacy of the payload with reduced systemic toxicities. Over several decades, the development of ADCs has cycled through highs and lows in which substantial excitement over the promise of ADCs was followed by disinterest when disappointing clinical results were announced. This has resulted in several companies abandoning their internal ADC development efforts. To date, 13 ADCs have been approved to treat hematologic or solid tumors, with 11 granted FDA approvals.

Several ADC deals have been announced, which has reinvigorated interest and investments in ADCs. The renewed interest in ADCs is due, in part, to the recent clinical success of Daiichi’s HER2-targeting ADC, trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca), which uses their proprietary topoisomerase I inhibitor payload, DXd. Enhertu is the first ADCs to gain FDA approval as a tissue-agnostic ADC, which provides optimism that more ADCs will be able to follow the success of trastuzumab deruxtecan.


Introduction
In the early 1900s Nobel laureate, Paul Ehrlich introduced the concept of directly targeting human diseases using a magic bullet. Antibody drug conjugates (ADCs) are the embodiment of Paul Ehrlich’s magic bullet concept because ADCs deliver a chemotherapeutic drug/payload directly to tumors thus reducing the chemotherapeutic drug’s systemic toxicity on normal tissues. There are several companies focused on developing ADCs. One of the most successful companies developing ADCs is Seattle Genetics.

Table 1: Approved ADCs

Seagen (previously: Seattle Genetics), which was founded in 1977, developed their proprietary protease cleavable dipeptide linkers (valine-citrulline and valine-alanine) and a class of tubulin inhibitors called Auristatins (MMAE and MMAF). Seagen’s technology is used by the majority of the approved ADCs (Table 1).

A total of thirteen ADCs have been granted marketing approvals (Table 1). Eleven ADCs were approved by the United States Food and Drug Administration (FDA). Marketing approval for belantamab mafodotin (Blenrep®; GSK), which was approved in 2020 for adult patients with relapsed or refractory multiple myeloma, was withdrawn in 2022 when a confirmatory Phase 3 trial failed to meet its primary end point. Two HER2 ADCs, Ujvira® (ZRC-3256; Zydus Cadila), which is the first biosimilar of trastuzumab emtansine (Kadcyla®; Genentech/Roche), and disitamab vedotin (RC48; Aidixi®; RemeGen), have gained approval in India and China respectively.

The first FDA approved ADC was gemtuzumab ozogamicin (Mylotarg®; Wyeth/Pfizer). [1] Gemtuzumab ozogamicin was approved in 2000 for the treatment of CD33 positive AML patients who are 60 years of age or older, in first relapse and who are not considered candidates for cytotoxic chemotherapy (Figure 1)

Gemtuzumab ozogamicin contains 50% unconjugated antibody while the other 50% of the conjugated antibody has a drug to antibody ratio (DAR) @6 thus gemtuzumab ozogamicin has a DAR between 2-3. [2] Since gemtuzumab ozogamicin was developed, conjugation efficiencies of ADCs have dramatically improved to where the range is between 75% and 90% depending on the conjugation conditions.[3] In 2010 gemtuzumab ozogamicin was removed from the market due to a lack of clinical benefit, a higher risk of serious side effects and a higher fatality rate compared to chemotherapy. [4][5] Gemtuzumab ozogamicin eventually received full approval by the FDA in 2017 for newly diagnosed and relapsed AML in adult patients and relapsed AML in pediatric patients aged 2–17 years. This is a different patient population compared to the original patient population for gemtuzumab ozogamicin treatment. In addition, pharmacokinetic/pharmacodynamic modeling suggested that a lower dose and different schedule would reduce hepatic veno-occlusive disease (VOD), which had resulted in substantial morbidity and mortality for gemtuzumab ozogamicin patients. [4][6]

Over a decade after gemtuzumab ozogamicin’s approval, Adcetris was approved by the FDA for the treatment of CD30 positive patients with systemic anaplastic large cell lymphoma (sALCL) in 2011. [7] Early clinical data for ADCs suggested that hematological cancer patients would benefit from ADCs, but it was unclear if ADCs would be effective in patients with solid tumors.  Trastuzumab emtansine (Kadcyla®; Genentech/Roche), which is a HER2-targeting antibody (trastuzumab) conjugated to the tubulin inhibitor DM1, was approved by the FDA in 2013 for the treatment of HER2-positive metastatic breast cancer patients who have previously received trastuzumab (Herceptin®; Genentech/Roche) and taxane, separately or in combination. [8] This provided the evidence that ADCs could also provide substantial benefit to patients with solid tumors. Of the approved ADCs, seven are treatments for solid tumors (Table 1).

There are over 200 active clinical trials focusing on ADCs. Although there is excitement over the increasing number of ADCs entering clinical development, it is also important to note that over 100 ADCs have discontinued clinical development. Most ADCs are discontinued in phase 1 and/or phase 2 with very few ADCs reaching phase 3 (Figure 2).

Figure 2 Comparison of the clinically active and non-clinically active ADCs. ([A] The clinical stage of development of the clinically active ADCs; [B] The clinical stages of development of the non-clinically active ADCs.
To understand why ADCs fail during clinical development, we need to examine several factors, including targets and the linker-payloads.

ADC targets
The most frequent ADC targets in clinical development are HER2, Trop2, Claudin18.2, B7H3, cMet and EGFR (Figure 3).Interestingly, the target of the largest number of terminated  ADCs is also HER2 (Figure 4), which suggests that, in the case of HER2, linker-payload selection is critical to success.One approach to de-risk ADC development is to use well established oncology targets such as EGFR and cMet. Globally, there are 13 approved EGFR targeting kinase inhibitors and four approved EGFR-targeting antibodies, yet no EGFR ADCs have been approved. [9][10][11] Two EGFR ADCs, MRG003 and depatuxizumab mafodotin (ABT-414) progressed to phase 3 (12, 13). Depatuxizumab mafodotin (ABT-414), which was in phase 3 to treat glioblastoma (GBM) patients, was discontinued due to a lack of survival benefit .

Figure 3. The top ADC targets in clinical development.

Two cMet kinase selective inhibitors, Tepotinib (Tepmetko®; EMD Serono/Merck KGaA) and Capmatinib (INC280; Tabrecta®; Novartis) are FDA approved, but no cMet antibodies have been approved.

The most advanced cMet ADC is Abbvie’s, Telisotuzumab vedotin (ABBV 399), which uses Seagen‘s val-cit-MMAE linker payload, is in phase 3. These data suggest that even when validated cancer targets are selected as ADC targets, developing an ADC against those targets can be challenging.

Figure 4. The top clinically discontinued ADC targets

The most popular ADC target is HER2 (Figure 3). The HER2 ADC preclinical and clinical space is crowded and competing against trastuzumab deruxtecan and trastuzumab emtansine presents a formidable challenge. One example is TOT Biopharm’s HER2 ADC (TAA013). TOT Biopharm reported that the development of TAA013, which uses the same SMCC-DM1 linker payload as trastuzumab emtansine, was terminated in phase 3 due to limited market potential in China. [14] A similar fate was reported for Zymeworks biparatopic HER2 ADC, zanidatamab zovodotin (ZW49).

Zymeworks recently reported they have halted the initiation of their phase 2 clinical trial for ZW49 due to the competitive HER2 ADC space. [15] BeiGene, which gained the China rights to ZW49 in 2018, gave back the China rights in September 2023.

Tubulin inhibitor versus topoisomerase I inhibitor ADC payloads
The primary mechanisms of action for the approved ADC payloads are the inhibition of microtubule formation (tubulin inhibitor) or the inhibition of DNA synthesis (i.e. topoisomerase I inhibitor). Most ADCs in clinical development are using a tubulin inhibitor payload but there is an increasing number of ADCs using topoisomerase I inhibitors in clinical development due to the unprecedented success of trastuzumab deruxtecan (Figure 5).

Figure 5. Comparison of ADCs using tubulin inhibitor payloads vs. ADCs using topoisomerase I inhibitor payloads. ([A] The clinical development status of ADCs using tubulin inhibitor payloads and [B] The clinical development status of ADCs using topoisomerase I inhibitors.
In the DESTINY-Breast03 clinical trial (NCT03529110), which was a phase 3 clinical study comparing trastuzumab emtansine, a HER2 targeting ADC which uses the tubulin inhibitor payload, DM1, and trastuzumab deruxtecan, a HER2 targeting ADC, which uses the topoisomerase I inhibitor payload, DXd, trastuzumab deruxtecan was shown to have superior efficacy compared to trastuzumab emtansine in HER2 positive breast cancer patients.

Trastuzumab deruxtecan also showed significant efficacy in breast cancer patients expressing low levels of HER2. [16]. These data have led to several companies investing in the development of ADCs using topoisomerase I inhibitors.The percent of clinically active ADC programs using tubulin or topoisomerase I inhibitors compared to the percent of discontinued ADC programs using these payloads, shows ADCs using tubulin inhibitors have a higher percentage of discontinued clinical programs compared to ADCs using topoisomerase I inhibitor payloads (Figure 5).

Notable ADC deals
Several high-profile announcements of company acquisitions and licensing agreements has sparked a renewed interest in ADCs. Companies, such as Pfizer and Astellas, which had terminated their previous internal ADC development efforts are now reintroducing ADCs into their portfolios through acquisitions or licensing agreements. Merck, a large pharmaceutical company, is entering into the ADC space through its recent deals with Daiichi Sankyo and Kelun-Biotech (Table 1).

Table 2. Abbreviated list of the top ADC deals.

ADC deals can be placed into two categories. The first category is an ADC company is acquired by another company that plans to incorporate the ADC technology and assets into their pipeline. The other category is when a company in-licenses one or more ADC assets to enhance their pipeline.

Other companies are focused on enhancing their oncology portfolios via licensing ADC assets or ADC technologies from biotechnology companies, with several being China based biotechnology companies.

Merger and Acquisitions:

  • Pfizer’s acquisition of Seagen

Pfizer was one of the early adopters of ADCs. In 2009 Pfizer acquired Wyeth, which had developed calicheamicin, as an ADC payload, which was used to develop gemtuzumab ozogamicin (Mylotarg™; a CD33 targeting ADC) and inotuzumab ozogamicin (Besponza®; a CD22 targeting ADC). Pfizer’s R&D team was developing their proprietary ADC technologies and had established an ADC pipeline before abandoning their internal ADC efforts.

Pfizer re-enters the ADC space though its acquisition of Seagen for an estimated $43 billion USD. Seagen is one of the most experienced and successful ADC companies where five out of the thirteen approved ADCs are using Seagen’s ADC technology. Seagen’s ADC technology consists of the payload, which is family of tubulin inhibitors called Auristatins (MMAE and MMAF) and protease cleavable valine-citrulline (val-cit) and non-cleavable linker maleimidocaproyl (mc).  The challenge is the Auristatins are no longer protected by patents therefore Pfizer will have to innovate and develop new ADC technologies.

  • Johnson and Johnson’s acquisition of Ambrx

Johnson and Johnson agreed to acquire Ambrx for an all-cash merger transaction for a total equity value of approximately $2 billion USD. Ambrx has developed a proprietary non-natural amino acid site specific oxime conjugation technology and payload, which is similar to MMAF.

While Ambrx’s ADC technology has some strengths such as the excellent serum/plasma stability of the oxime conjugation, it also has some challenges. The first is the need to engineer the antibody to allow for the site-specific incorporation of the non-natural amino acid. The second challenge is obtaining high antibody titers from the stable cell lines used to express the antibody and lastly, you’ll have to supplement the growth media with the non-natural amino acid, which is an additional cost.

There are site specific conjugation technologies, such as those developed by Synaffix, which was recently acquired by Lonza, GlycoT Therapeutics and Shanghai GlycanLink Biotech Co, which eliminates the need for antibody engineering and have good ADC pharmacokinetic properties.

Ambrx’s clinical ADC pipeline consists of a HER2 ADC (ARX788), which is in phase 3, a PSMA ADC (ARX517), which is in phase 2 and a CD70 ADC (ARX305), which is in phase 1. The development of ARX788 was paused due to the significant competition in the crowded HER2 ADC space but Ambrx recently reported efforts to reinitiate the development of ARX788. [16]

ARX517 has reported 52% of heavily pretreated prostate cancer patients had >50% reduction in PSA and 81% of patients had a >50% reduction in circulating tumor DNA (ctDNA) in the phase 1/2 study (17). While these data are encouraging, safety and efficacy must be confirmed in late-stage clinical studies.

  • Abbvie’s acquisition of Immunogen

Abbvie agreed to acquire Immunogen for US $10.1 billion. Immunogen is known for developing the folate receptor a targeting ADC, mirvetuximab soravtansine (Elahere®), which was approved to treat folate receptor-α positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer patients. Immunogen also has a CD123 and ADAM9 ADC in their pipeline. Both ADCs are in early clinical development.

Immunogen, much like Seagen, is well established in the ADC space. Abbvie is not a novice to ADCs and has had a robust internal effort for several years. Abbvie’s cMet ADC, Telisotuzumab vedotin, is currently in phase 3.

Licensing
Licensing a late-stage ADC asset provides the lowest risk to a company’s pipeline but comes with a higher price.

  • Merck & Co

Merck & Co (know as Merck Sharp & Dohme or MSD outside the United States and Canada), which made an upfront payment of US $ 4 billion, has licensed several of Daiichi Sankyo’s ADCs including a Her3 ADC, which is phase 3, a CDH6 ADC, which is phase 2 and a B7H3 ADC, which is in phase 1 / 2. Merck seems to have taken a more balanced approach to address the risk in their ADC pipeline by licensing a late-stage ADC along with earlier stage ADCs. Daiichi Sankyo is well known and established company in the ADC space with a promising ADC pipeline and ADC technology platform. This deal has a potential value of US $ 22 billion.

Merck also has a ROR-1 ADC, currently in phase 2/3, from the US $ 2.75 billion acquisition of Velosbio in 2020.

  • Bristol Myers Squibb (BMS)

BMS made an upfront payment of $800 million USD to license SystImmune’s EGFR x Her3 bispecific ADC, BL-B01D1 (Zalontamab brengitecan), which is in phase 1 in the US and Phase 3 in China. BL-B01D1 was reported to have adequate safety, tolerability and demonstrated encouraging efficacy in heavily pretreated metastatic/locally advanced solid tumor in a phase 1 study. [18]

This seems to be a rather risky investment given the lack of clinical data showing significant benefits of bispecific ADCs over conventional monospecific ADCs, the use of a novel payload, Ed-04, which is a camptothecin derivative, the higher manufacturing costs for developing a bispecific ADC, and the low LOA for ADCs in early clinical development.

  • Pfizer

Pfizer announced a licensing deal with MediLink Therapeutics/Nona Bioscience for their mesothelin targeting ADC (HBM9033). HBM9033 received IND clearance from the FDA in November 2023 and is scheduled to being phase 1 clinical development. Pfizer’s upfront payment was US $ 53 million with potential payment of US $ 1.05 billion. Two mesothelin targeting ADCs are in clinical development, anetumab ravtansine and RC88. These ADCs are using DM4 and MMAE respectively and HBM9033 is the only mesothelin ADC using a novel topoisomerase I inhibitor payload. Two mesothelin targeting ADCs, BMS-986148, using the duocarmycin payload, and DMOT4039A, using the MMAE payload, have discontinued clinical development. Pfizer seems to have taken a risk investing in this asset given that mesothelin is not a clinically validated target and ADCs in early clinical development usually don’t progress past phase 2.

Discussion
This renewed interest in ADCs is fantastic but it also raises several questions. Is this interest in ADCs transient where some companies are looking for a quick way to raise capital due to the current popularity of ADCs or will companies invest in ADCs as a long-term strategy to support their oncology portfolio and improve the ADC technology?

The development of ADCs is not a simple endeavor. There’s a balance between selecting the right target, the right antibody, the right antibody binding epitope, linker, payload, conjugation method, and drug-to-antibody ratio (DAR). HER2 is a great example. There are four approved HER2 ADCs and nine HER2 ADCs have discontinued clinical develop. While HER2 is a clinically validated target for ADCs, simply producing an ADC against that target doesn’t guarantee the ADC will be successful.

The data also suggests that selecting clinically validated targets, such as cMet or EGFR, which were validated using other modalities, such as kinase inhibitors or even signal pathway blocking antibodies, may not be an easy path for developing an ADC against those targets.

The increased number of companies developing topoisomerase I inhibitor payloads will hopefully lead to improvements on DXd. Trastuzumab deruxtecan, which uses the DXd payload, has a black box warning for interstitial lung disease (ILD), pneumonitis, and embryo-fetal toxicity. ILD and pneumonitis has also been reported in patients treated with ADCs using DXd (i.e. datopotamab deruxtecan and ifinatamab deruxtecan) but not for patients using the topoisomerase I inhibitor, SN38. [19][20][21]

The Trop2 targeting ADC, sacituzumab Govitecan (Trodelvy®; Gilead), which uses the SN38 payload, also has a black box warning for severe or life-threatening neutropenia and severe diarrhea. [22] These data suggest the toxicities associated with these ADCs are due to the chemical properties of the payloads and not the mechanism of action.

In the quest to differentiate from monospecific ADCs and possibly address the heterogeneity of tumor target expression and broaden the number patients that can benefit from an ADC, more companies, such as SystImmune, are developing bispecific ADCs. Several challenges exist for developing bispecific ADCs. The first will be the selection of the bispecific antibody format. Some bispecific antibody formats will require the development of two cell lines that stably express each arm of the bispecific antibody. This will increase the manufacturing costs and increase the complexities of the assays associated with ensuring proper chemical, manufacturing, and controls (CMC) have been achieved. The next challenge will be selection of the targets and understanding which target combinations would be best for a bispecific ADC. Lastly challenges with balancing the antibody affinities and understanding the biology of each target need to be addressed.

Some companies appear to have a clear strategy to incorporate ADCs into their portfolios and to invest in developing the next generation of ADCs. The innovation in the ADC space appears to come from biotech companies that have either licensed their technology, assets or have been acquired by larger companies trying to diversify their oncology pipelines. This may be one of the approaches larger companies use to address the loss of patent protection for some their assets.

Another consideration for companies developing ADCs is the selection of the CDMO they will use to produce their ADCs to support their clinical trials and eventual commercial global launch. Some of the most popular companies, such as WuXi and Samsung, have significant manufacturing capabilities in Asia.

AstraZeneca recently announced plans to invest US $1.5 billion to build a manufacturing site in Singapore to support their ADC pipeline. Lonza, which recently acquired Synaffix, and Piramal have manufacturing capabilities outside of Asia. With the ever-increasing pressure for US companies to sever relationships with China based CDMOs, the selection of the CDMO and the timing of the discussions will become critical to reduce the risk of significant manufacturing delays.

Developing new cancer therapies is a difficult endeavor. Oncology has one of the lowest success rates across several therapeutic areas. The likelihood of approval (LOA) for oncology drug development, from phase 1 to approval, ranges from 3.1 – 5.3%. [23] This includes small molecules, biologics, and other modalities. When the LOA for clinical oncology programs was evaluated for a period of nine years, from 2011 to 2020, the estimated LOA for ADCs was 10.8%. [24] Another report estimated the LOA for ADCs to be 29%. [25] This places the ADC clinical failure rate between 71% and 89.2%.

As ADCs progress through clinical development, the LOA improves. The LOA for ADCs in phase 2 is 25.9% and 62.5% for ADCs in phase 3. [24] Investments in late-stage clinical ADCs is a more prudent investment than early-stage ADCs.

Further innovation in antibody technology (i.e. antibody fragments), target selection, linker-payload design to reduce off target toxicities and drug resistance. Changes in clinical trial study design are also needed to improve the LOA for ADCs. The complexities of developing ADCs may benefit from the use of artificial intelligence and machine learning methods to help design the next generation of ADCs and improve the clinical success rate of ADCs.

Acknowledgements
I’d like to thank Rajiv Kumar and the team at Beacon for their assistance with the data and the preparation of this review.

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Authors: Dowdy Jackson, Ph.D 1

Corresponding Author: Dowdy Jackson, Ph.D.

Key terms: ADC, antibody-drug conjugate, drug-to-antibody ratio, DAR, chemical conjugation, site-specific conjugation, Fc affinity peptide conjugation, DXd, Auristatins, MMAE, MMAF, HER2-targeting

Published In: ADC Review| Journal of Antibody-drug Conjugates

DOI: https://doi.org/10.14229/jadc.2024.07.02.001.


How to cite:

Dowdy Jackson, Ph.D 1
The Highs, Lows, and Resurgence of Antibody-drug Conjugates – J. ADC. June 2, 2024. DOI: 10.14229/jadc.2024.07.02.001.

1 Jackson Consulting Group


Last Update and Editorial Review: June 28, 2024

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Article History:

  • Original Manuscript Received June 6, 2024
  • Review results received June 17, 2024
  • Revised Articles Submitted: June 26, 2024
  • Manuscript accepted for publication  June 28, 2023
  • Article published online: July 2, 2024

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