Antibody-drug conjugates (ADCs) are a class of anticancer drugs where cytotoxic drugs are attached to antibodies that target specific antigens on tumor cells. This allows highly selective delivery of chemotherapy to tumors while minimizing systemic exposure. Several key factors influence ADC effectiveness, including the antibody, cytotoxic drug, and linker used. To date, 11 ADCs have been approved by the FDA to treat various cancers. However, challenges remain in developing additional ADCs, such as finding the right molecular targets and components, managing toxicity, and addressing complex manufacturing requirements.
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Antibody-Drug Conjugates for Cancer Therapy - Prospects, Challenges, and Recent Approvals
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Antibody-Drug Conjugates for
Cancer Therapy - Prospects and
Challenges
Antibody-drug conjugates (ADCs) are a rapidly evolving class of anticancer
therapeutics consisting of antibodies attached to potent cytotoxic drugs via
chemical linkers. The antibodies are designed to target specific antigens
(receptors) highly expressed in tumor cells. ADCs provide highly selective drugs
to tumors, thus minimizing their systemic exposure and potentially leading to
improved therapeutic indices (higher efficacy and fewer adverse effects). Most
ADCs follow a similar mechanism of action involving antibody-mediated
receptor binding, ADC internalization and subsequent release of payload and
cytotoxicity, as shown in Figure 1.The success of ADCs relies on several key
factors as belows.
1) Target antigens (e.g. CD30, HER2, CD22, CD33, CD79b, Nectin 4, Trop2,
BCMA, CD19)
2) Antibody type (e.g. IgG1, IgG2, IgG4, nanobodies, bispecific antibodies)
3) Payload type (e.g. Monomethyl auristatin E (MMAE), DM4, calicheamycin,
DM1, MMAF)
4) Linker type (e.g. valine-citrulline, Sulfo-SPDB, hydrazone linker)
5) Conjugation platform (e.g. lysine-, cysteine- and site-specific conjugation)
6) Target indications (e.g. breast cancer, lymphoma, leukemia, uroepithelial
cancer, lung cancer, ovarian cancer).
ADCs mechanism of action, image source: reference 1
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FDA Approved ADCs
To date, 11 ADCs have been approved by the FDA, namely Adcetris®,
Kadcyla®, Besponsa®, Mylotarg®, Lumoxiti®, Polivy®, Padcev®, Enhertu®,
Trodelvy®, Blenrep® and Zynlonta™, for oncology indications only (Table 1,
Figure 2a). In addition, more than 80 ADCs are currently in clinical studies as
single agents or in combination for various tumor types.
FDA Approved ADCs, Image
source: https://www.biochempeg.com/article/202.html
Two of the latest ADCs to be approved, Trodelvy and Zynlonta, were
developed with PEG moiety as part of their linker technology to
improve solubility and stability in vivo.
On April 23, 2021, the FDA approved Zynlonta, the first CD19-targeted ADC,
for the treatment of adults with relapsed or refractory diffuse large B-cell
lymphoma (DLBCL), based on the pivotal Phase II clinical trial LOTIS-2.
Zynlonta (loncastuximab tesirine) is a humanized CD19 monoclonal antibody
conjugated to pyrrolobenzodiazepine (PBD) dimeric cytotoxin via a linker.
PEG linker for Zynlonta: Mal-NH-PEG8-COOH
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Structure of Zynlonta
On April 22,2020, the FDA approved sacituzumab govitecan (Trodelvy), a
Trop-2-directed antibody conjugated to a topoisomerase I inhibitor (SN-38), for
the treatment of some patients with triple-negative breast cancer.
PEG linker for Trodelvy: 2-((Azido-PEG8-carbamoyl)methoxy)acetic acid
Structure of Trodelvy
Novel ADCs in clinical trials
More than 80 ADCs are currently in active clinical trials, with the majority in
Phase I and Phase I/II (Table 2, Figure 3a). More than 80% of clinical trials are
investigating the safety and efficacy of ADCs in a variety of solid tumors, while
the remaining trials involve hematologic malignancies (Figure 3b). This may
indicate a shift in experimental ADCs in solid tumors in recent years with the
early success of T-DM1 and the recent approval of T-Dxd, sacituzumab
govitecan, and enfortumab vedotin. In this list, there are about 40 different
targets with several ADCs against the same target (Table 2, Figure 3c).
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ADCs in clinical trials, image source: reference 1
Challenges in the development of ADCs
Why have more not already been approved? The issue of toxicity has been a
challenge, as has the complexity of ADCs and the consequent manufacturing
challenges.
Crafting the right molecule
Finding the right targets, proteins, linkers and payloads all belong to the
discovery phase. This phase is very challenging because properly defining a
drug is key to bringing it successfully to the clinic. ADCs represent an equally
highly complex and unpredictable product class. Finding the right target and
crafting a potent molecule has proven to be much more difficult than many
researchers expected at the start of an ADC study. The initial understanding was
that finding a good target antigen for an ADC-based compound required a target
that could be rapidly internalized once it reached the cell, with the result that in
many cases, targets that were ineffective against monoclonal antibody (mAb)
therapies due to rapid internalization became the perfect targets for ADC
therapies.
Site-specific conjugation
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Site-specific conjugation is considered as a second generation ADC conjugation
technique. Many ADCs in preclinical and clinical stages are based on site-specific
conjugation technology of one form or another.
Even though more site-selective ADCs are expected in the future, stochastic
conjugation of ADCs can still be successful. Site-selective conjugation does not
appear to exhibit significant differences in clinical activity and safety compared
to classical non-site-selective conjugation. The lack of commercially available
site-specific conjugated molecules is simply a consequence of the head start
that stochastic conjugation has had, but it is also possible that the simplicity of
manufacturing and the homogeneity of analytical testing methods do not
directly lead to better outcomes for patients.
Linker chemistry matters
Linker chemistry is an important component of ADCs and has a major impact on
performance. Linker chemistry plays a key role in in-vivo stability, but was
initially assumed to have a passive role with the exception of either being stable
or labile in the acidic cytosolic cellular environment.
Over the past 20 years, the technology has evolved and matured to the point
where linker technology is stable and molecules in development exhibit low
levels of de-conjugation in patients. Both protease-cleavable and non-cleavable
linkers are in development and on the market.
Classical conjugation chemistry approaches include maleimide and
hydroxysuccinamide-ester moieties (Seattle Genetics, Roche and Pfizer). There
are also a variety of newer linker technologies, some in the proof-of-concept
stage and some already in preclinical evaluation.
Undesired immune responses
ADCs are designed to be more selective than traditional chemotherapeutic
agents. The mAb are able to target cancer (or other disease) cells, with
payloads delivered with high selectivity and reduced systemic toxicity compared
to standard chemotherapeutic agents.
Unfortunately, undesired immune responses pose a problem that is difficult to
overcome. These responses are largely due to the large number of variables
being studied and the relatively small number of clinical trials being conducted.
Lower-than-expected therapeutic window
The main issue affecting ADC approvals today is that the therapeutic window for
these therapies is lower than expected. However, this window has proven to be
much more complex than originally hoped, and therefore its clinical impact is
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not as great as originally thought. The complexity of ADCs themselves is also a
major issue here.
Complex supply chain
The ADC supply chain is also very complex. ADCs are unique in that they are
manufactured as a amalgamation of classical small molecule manufacturing and
traditional mAb manufacturing, with the added complexity of high potency drug
manufacturing. All three of these characteristics are complex in themselves,
and combining them brings the complexity to an even higher level. Supply chain
management of ADCs is one of the most complex processes in the
pharmaceutical industry and must be managed by experienced teams with the
lowest possible risk.
As more ADCs are approved commercially, it is believed that a roadmap will be
established for other companies to follow, leading to more success in the near
future.
References:
1. Dean AQ, Luo S, Twomey JD, Zhang B. Targeting cancer with antibody-drug conjugates:
Promises and challenges. MAbs. 2021 Jan-Dec;13(1):1951427. doi:
10.1080/19420862.2021.1951427. PMID: 34291723.