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Antibody-Drug Conjugates for Cancer Therapy - Prospects and Challenges

Release time:2021/8/28 15:47:31
Author:Huateng

Antibody-drug conjugates (ADCs) are a rapidly evolving class of anticancer therapeutics consisting of antibodies attached…

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).

ADC mechanism of action

ADCs mechanism of action, image source: reference 1

FDA Approved ADCs

To date, 12 ADCs have been approved by the FDA, namely Adcetris®, Kadcyla®, Besponsa®, Mylotarg®, Lumoxiti®, Polivy®, Padcev®, Enhertu®, Trodelvy®, Blenrep®, Zynlonta™ and Tivdak, 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.
approved-adcs.jpgFDA 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

zynlonta_detailed_image

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

trodelvy_detailed_image_1

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).

ADCs in clinical trials

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

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 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.