Release date:2023/8/29 17:02:10

Antibody-drug conjugate (ADC) consists of linker, payload, and monoclonal antibody (mAb). It combines the advantages of high specific targeting ability and strong killing effect to achieve accurate and efficient killing of cancer cells, and has become one of the hot spots in the research and development of anti-cancer drugs.

Since the first ADC drug Mylotarg (gemtuzumab ozogamicin) was approved by the FDA in 2000, up to now, a total of 15 ADC drugs have been approved for marketing in the world for hematological malignancies and solid tumors. In addition, more than 400 ADC drugs are in various stages of research and development. Among the 15 approved ADC drugs, 13 are marketed in the United States, 1 in China and 1 in Japan.

Among the 13 FDA-approved ADCs, 6 target hematological indications (upper row in Figure 1), 7 target solid tumor indications (lower row in Figure 1), and 3 of them target HER2 antigen. With the development of antibody drugs, the advancement of conjugation technology, and the continuous improvement of the ADC concept and other factors, the enthusiasm for research and development of ADC drugs continues to grow.

 FDA-approved ADC drugs

Figure 1. FDA-approved ADC drugs
(Souce: References[1])

In this context, we will briefly review the development stages of ADC drugs, the evolution of the ADC drug development and and the R&D trends of the next generation ADC drugs. 

Development Stages of ADC Drugs

ADC drugs have gone through three stages: the embryonic stage, the exploratory stage, and the mature development stage.

1. Emerging stage (1910-1980)

ADC is not a new concept. As early as the beginning of the 20th century, German scientist Paul Ehrlich, a Nobel laureate in medicine, had proposed the concept of ADC and called ADC drug " Magic Bullet". But until the 1950s, research on ADC drugs began to improve. In 1958, Mathe first coupled the mouse antibody with pterygine for the treatment of leukemia. Due to difficulties in immunogenicity and antibody preparation, ADC drugs remained stagnant for several decades until the introduction of monoclonal antibodies in 1975, and later the emergence of humanized antibodies.

2. Exploring stage (1980-2000)

ADC drugs combine the advantages of high specific targeting ability and strong killing effect to achieve precise and efficient killing of cancer cells, and have become one of the hot spots in the research and development of anticancer drugs. In the 1980s, Greg Winter pioneered the technology of humanized monoclonal antibodies, and the development of ADC drugs made a major breakthrough. However, the technology is still immature, and the first ADC marketed drug, Mylotarg, was approved in 2000 but withdrawn from the market in 2010 due to fatal liver toxicity during its use

3. Mature development period (2000-present)

Since the first ADC drug Mylotarg (gemtuzumab ozogamicin) was approved by the FDA in 2000, at present, a total of 15 ADC drugs have been approved for hematological malignancies and solid tumors worldwide. More than 400 ADC candidates are currently in various stages of clinical trials.

Evolution of the ADC Drug Development

From the perspective of drug composition and related technical characteristics, the development of ADC drugs can be subdivided into four generations.

1.The First-generation ADC drugs

The first generation ADC representative drug was Mylotarg, the first ADC drug approved by the FDA in 2000, which was used for the treatment of acute myeloid leukemia. However, Mylotarg was voluntarily withdrawn from the market in 2010 due to its severe fatal liver injury and no obvious survival benefit, and was re-listed in 2017.

The first generation of ADC drugs was an attempt in 1958 to use antimouse leukocyte immunoglobulin coupled with methotrexate to treat leukemia. The first generation of ADC drugs, represented by Mylotarg, had high off-target toxicity and low drug efficacy, and most of them ended in failure.

The disadvantages of the first generation of ADC drugs are: the antibody is a murine antibody; the linker cannot be cleaved; the cytotoxin is insufficient; the site is lowly expressed.

2. The Second-generation ADC drugs

Representative second-generation ADC drugs include: Kadcyla, Adcetris, and Zynlonta.

This generation of ADC drugs has improved mAb technology and carefully selected monoclonal antibodies to improve tumor cell targeting and reduce cross-reactivity with healthy cells. More importantly, there was a lack of clinical research on the early use of small-molecule drugs that were then used to treat cancer as toxic loads, and more effective small-molecule substances were discovered later.

However, because the second-generation ADC drug is still coupled by traditional chemical methods, the antibody conjugation ratio (DAR) is poor in uniformity (0-8 or even higher) and the linker is not stable, so it is easy to be cleaved in the blood and cause serious toxic side effects.

The second-generation ADC drug development started with Kadcyla, which was the first approved ADC drug targeting breast cancer. The most successful ADC drug in the hematologic oncology field is Adcetris, which focuses on classical Hodgkin's lymphoma and anaplastic large cell lymphoma.

The advantages of the second-generation ADC drugs are: diversification of target antigen development; humanized antibodies; cleavable linker technology. The disadvantages are: the drug loading rate is too low or too high; the therapeutic window is narrow; the effectiveness is low.

3. The Third-generation ADC drugs

Representative ADC drugs of the third generation include: Enhertu, Besponsa, Padcev.

On the basis of the first and second generation of ADC drugs, this generation of ADC drugs uses site-specific conjugation technology to produce ADC drugs with uniform DAR values, showing less off-target toxicity and better pharmacokinetic efficiency. And switch to fully humanized antibodies to further reduce immunogenicity.

Represented by Enhertu, Besponsa, Padcev, etc., the stability and pharmacokinetics of the drug have been improved. A typical representative of the third-generation ADC drug is Padcev, which is the second ADC drug targeting solid tumors and is suitable for patients who fail PD-1/PD-L1 antibody therapy.

The advantages of the third-generation ADC drugs are: small molecule-mAb site-specific conjugation technology; development of bispecific antibodies; eukaryotic RNA splicing inhibitors to enhance specificity. Disadvantages: Difficult to reproducible conjugation technique; Insensitive to tubulin inhibitors.

 Evolution of ADC drug development

Figure 2. Evolution of ADC drug development
(Souce: References[2])

4.The Fourth-generation ADC drugs

Representative ADC drugs of the fourth generation include: DS-8201, Trodelvy, SKB264.

This generation of ADC drugs uses topoisomerase I inhibitors in their payloads, mainly camptothecin derivatives such as topotecan, irinotecan, and belotecan; In terms of drug design, they are generally designed to be low in toxicity and high in toxicity. For DAR molecules, Trodelvy and SKB264, two ADC drugs targeting Trop-2, have DAR values of 7.6 and 7.4 respectively, and DS8201 has a DAR value of 7.8, which can provide more payloads to tumor cells and exert curative effect.

Generally speaking, compared with the previous three generations of ADC technology, this generation of ADC technology has made greater progress, but there is still room for further optimization:

(1). The payload mechanism is relatively simple, mainly based on cytotoxic compounds, fewer options, and easy to cause drug resistance;

(2). The stability of the linker in the circulatory system is insufficient, which can easily cause systemic toxic reactions;

(3). ADC has large molecular weight, slow tumor enrichment rate and low permeability, and traditional technology requires that antibodies can be endocytosed to be effective. Non-endocytotic antibodies cannot be used for the development of ADC, resulting in limited antibody selection.

ADC drugs have demonstrated excellent clinical efficacy in the fields of breast cancer, gastric cancer, urothelial cancer, lung cancer, and hematological tumors. It is believed that as drug developers continue to deepen their understanding of ADC drugs, the molecular structure design of ADC will be more reasonable, and the stability in vivo will continue to be improved, thus reducing toxic and side effects, improving drug efficacy and activity, expanding the therapeutic window, and bringing new hope to cancer patients.

R&D Trends of The Next-generation ADC Drugs

From the development of ADC drugs, it can be seen that with the change of technology, the specificity and cytotoxicity of the new generation of ADCs are getting better and better than those of the previous generations. Of course, there are still certain challenges in the development of ADC drugs. In this regard, this section will provide an overview of the possible development trends of ADC drugs.

1. Using ADC to target mutant proteins

Current studies have shown that ADC internalization and intracellular transport pathways have key influences on the cytotoxic activity of ADCs. Compared to wild-type proteins, mutant proteins typically have higher levels of ubiquitination and are more easily internalized and degraded. This means that if an ADC is used to target a mutated protein, it could lead to a significant clinical response. It is conceivable that targeting ADCs carrying cancer-causing mutated proteins, such as certain EGFR mutants, could maximize the tumor specificity of therapy to the level of selective TKI.

2. Dual-epitope ADC or dual-target ADC

Advances in bispecific antibody technology have brought more possibilities for ADC innovation. These ADC designs can improve antibody internalization and increase tumor specificity. Therapies currently in development have been exploring these possibilities. Bispecific ADCs targeting different sites on the same antigen can improve receptor clustering and lead to rapid internalization of the target. In addition, bispecific ADCs dual targeting HER2 and LAMP-3 showed better lysosomal aggregation and load delivery in preclinical experiments.

3. Using two different payload combinations

A dual-payload ADC using two different cytotoxic agents as payloads to reduce drug resistance. By precisely controlling the ratio of the two drugs, more effective therapeutic effects can be achieved by delivering the two synergistic payloads into cancer cells. And with the application of payloads with two different mechanisms, the incidence of drug resistance will be significantly reduced. For example, a homogeneous anti-HER2 ADC containing both MMAE and MMAF was designed and exerted more significant anti-tumor activity than co-administration of the corresponding single payload ADC in a xenograft mouse model.

4. Peptide–drug conjugates (PDCs) 

Another ADC development strategy is to abandon the traditional structure of mAb and choose to couple the payload to a polypeptide fragment with a smaller molecular weight. The main purpose of these strategies is to reduce the molecular weight of ADCs, thereby improving penetration efficiency and delivery of payloads to tumor tissues. For example, PEN-221 is an ADC consisting of DM-1 conjugated to a polypeptide chain targeting somatostatin receptor 2. Its molecular weight is only 2 kDa, which is much lower than the 150 kDa IgG molecule in traditional ADCs. The current technical challenge with such ADCs is that they may be rapidly cleared in plasma. However, if we can overcome this hurdle, it has potential in the treatment of inaccessible tumors, including those with poor vascular innervation and CNS tumors.

5. Developing of non-internalizing ADCs

Traditionally, ADCs have required mAbs with high internalization capacity in order to deliver payloads into cancer cells. However, mAbs often have difficulty diffusing into solid tumor masses due to antigenic barriers. Therefore, non-internalizing antibodies can be developed for ADCs. It is based on the principle that the payload is directly released outside the cell under reducing conditions in the tumor microenvironment, and then diffuses into the interior of the cancer cell to cause cell death.

Finally, there are still many opportunities for innovation in payload selection.

Currently, a variety of ADC therapies have been successfully developed, benefiting tens of thousands of cancer patients. The approval of 15 ADC drugs and the excellent clinical performance of multiple ADCs have also attracted more attention to the field, which is very important for this relatively young but highly complex field. With the continuous efforts of researchers in these fields, it is not difficult to imagine that future ADCs will show more surprises in cancer targeted therapy.

As a worldwide leader of PEG linker supplier, Biopharma PEG offers the full range of PEG derivative development services and provide the most comprehensive media for conjugation research. We supply versatile ADC linkers, including but not limited to: amine reactive, carbonyl reactive, caboxyl and active ester reactive, thiol reactive, branched, and more.

[1]. Charles Dumontet, Janice M. Reichert, Peter D. Senter, John M. Lambert & Alain Beck,
Antibody–drug conjugates come of age in oncology, Nature Reviews Drug Discovery | Volume 22 | August 2023 | 641–661
Antibody drug conjugate:the “biological missile” for targeted cancer therapy. Signal Transduction and Targeted Therapy (2022) 7:93

Related articles:
Summary of ADC Targets For Solid Tumors & Hematological Tumors
[2]. ADC Therapies: Current Development & Future Prospects
[3]. Overview of ADC-Based Combination Therapies
[4]. Design Elements And Design Criteria For ADC Drugs


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