The Market of Antibody–Drug Conjugates: History
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Contributor:
Balázs Kiss
,
János Borbély

The cytotoxic effect and therapeutic window of mAbs by constructing antibody–drug conjugates (ADCs), in which the targeting moiety is the mAb that is linked to a highly toxic drug. According to a report from mid of last year, the global ADCs market accounted for USD 1387 million in 2016 and was worth USD 7.82 billion in 2022. It is estimated to increase in value to USD 13.15 billion by 2030. One of the critical points is the linkage of any substituent to the functional group of the mAb. Increasing the efficacy against cancer cells’ highly cytotoxic molecules (warheads) are connected biologically. The connections are completed by different types of linkers, or there are efforts to add biopolymer-based nanoparticles, including chemotherapeutic agents.

  • antibody–drug conjugate (ADC)
  • nanomedicine
  • development
  • market
  • drug

1. Introduction

Medical (red) biotechnology is currently one of the most rapidly developing industries, with disruptive innovations emerging from time to time. Each decision, such as the development of a drug, has the potential to be worth billions of USD. The pharmaceutical industry is among the most research-intensive industries, with an average new product development (NPD) cycle of 11.9 years [1]. The uncertainty in the industry is determined primarily by its nature, which leads to very long development timelines (averaging approximately 10 years from research to market), very large investments (approximately USD 1–2 billion for new molecules), and extremely stringent regulations for product licensing. For these reasons, it is important to minimize business risks during the early stages of drug development. As antibody–drug conjugates (ADCs) are currently one of the most heavily researched areas in biotechnology, it is certainly worthwhile to consider this area from that perspective.
An example from 2017 illustrates the importance of prudent R&D where the pivotal trial of Bayer’s ADC anetumab ravtansine did not meet its primary endpoint, as the drug failed to improve progression-free survival in mesothelioma patients. This resulted in a decline in the stock prices of Bayer’s collaborators, ImmunoGen and MorphoSys [2].
ADC is a type of targeted therapy that combines the specificity of monoclonal antibodies with the cytotoxicity of a small molecule drug. ADCs are designed to deliver a toxic payload specifically to cancer cells, minimizing damage to healthy cells.
The market for ADC is expected to grow significantly in the coming years, driven by the increasing incidence of cancer, the growing demand for targeted therapies, and the development of new and improved ADC technologies. The cancer type that is most targeted by ADCs is breast cancer, followed by lung and ovarian cancers. The market is divided into segments on the basis of the type of drug, with the largest portion of the market held by microtubule inhibitors, followed by DNA-damaging agents and alkylating agents. Additionally, the market is segmented on the basis of its applications, with the highest market share held by solid tumors, followed by hematological malignancies. In terms of geography, North America holds the largest market share, due to the presence of a large number of biotechnology and pharmaceutical companies in the region, followed by Europe and Asia Pacific.
Companies such as Seattle Genetics, ImmunoGen, and Roche are some of the key players in the ADC market. The activity of the market is shown by the fact that continual acquisitions and mergers are also characteristic of the present times. An excellent example of this is the recently announced news that Pfizer and Seagen have entered into a definitive merger agreement under which Pfizer will acquire Seagen, a global biotechnology company that discovers, develops, and commercializes transformative cancer medicines, for USD 229 in cash per Seagen share for a total enterprise value of USD 43 billion [3]. It is the largest acquisition in biopharma since June of 2019, when AbbVie acquired Allergan for USD 63 billion. Early in 2019, Bristol Myers Squibb executed the largest transaction in industry history with its USD 74 billion purchase of Celgene [4].
It is worth mentioning that ADCs are still a relatively new class of therapeutics, and they are still facing a number of challenges. For example, many ADCs that have been developed so far have not shown significant efficacy in clinical trials [2][5], and many have experienced setbacks during development. Additionally, the cost of ADC therapy is high (e.g., yearly ADC treatment regimen costs~USD 100–500 k [6][7]); production costs also are high [8], which could be a barrier for some patients.
In order to overcome these weaknesses, recent developments are creating new constructions to improve efficacy. A new development introduces the advantages of peptide-drug-conjugated constructions [9] vs. ADCs.
In order to increase the payload, drug molecules are located in a nanoparticle, which is conjugated with the mAb. Those new structures are referred to in the literature as antibody-conjugated nanoparticles (ACNP). It is expected that through this structure, the selectivity and the efficacy are improved. Nanoparticles, e.g., liposomes, that are used as chemotherapeutic agent nanocarriers for doxorubicin (Doxil), are successfully conjugated with mAbs, forming the so-called immunoliposomes [10][11][12][13][14]. Targeting immunoliposomes are in clinical trials [15][16]. Other polymeric nanoparticles based on natural or synthetic biopolymers are conjugated with mAb and are carriers of anticancer drugs, such as as doxorubicin (DOX), paclitaxel (PTX), epirubicine, and cisplatin [17][18][19][20][21]. Many other nanocarriers have been conjugated with mAb, e.g., dendrimers [22], gold nanoparticles [23], and magnetic nanoparticles [24].

2. The Market of ADCs

The mAbs, e.g., Herceptin (Trastuzumab (TZM)), are a class of anticancer agents. Kadcyla represents the gold standard for the treatment of HER2+ breast cancer patients [25]. Recent developments aim to extend the cytotoxic effect and therapeutic window of these type of mAbs by constructing ADCs in which the targeting moiety is the mAb that is linked to a highly toxic drug. As of the end of 2022, there were 14 ADCs marketed, and there are approximately 100 others in clinical trials for different indications. According to a report from the middle of last year, the global ADC market accounted for USD 1387 million in 2016 and was worth USD 3.51 billion in 2020, registering a compound annual growth rate (CAGR) of 14.12%. It is estimated to grow at a rate of 17.08% and will increase in value to USD 13.15–16.4 billion by 2030 [26][27] as Figure 1 shows.
Pharmaceutics 15 01761 g001 550
Figure 1. Global ADC market [26]. Quoted with permission from Strategic Market Research. Available online: https://www.globenewswire.com/en/news-release/2022/06/21/2465821/0/en/Antibody-Drug-Conjugate-Market-a-13-15-billion-Industry-by-2030-with-a-CAGR-of-14-12.html (accessed on 21 June 2022).
One might inquire as to the significance of ADCs and the reasons for their substantial market growth rate. Let us provide a concise summary of the principal determinants that underlie this phenomenon. Primary drivers stimulating the global market expansion are the following: ADCs are developed to target the cancer cells alone, bypassing the healthy cells. Using this phenomenon, ADCs are used primarily in cancer treatment. According to Eurostat, cancer was responsible for the deaths of approximately 1.2 million people in Europe, which was 26% of the total deaths in the region. According to the CDC, breast cancer is the second most common type of cancer in women in the US and is responsible for nearly 42,000 deaths each year. Thus, with rising cancer cases globally, the need for ADCs will boost the overall market growth. As per UN statistics, globally, the number of people over the age of 65 will rise from 9.3% of the total population in 2020 to 16.0% of the population by 2050. To ensure a good quality of life at this increased average age, more targeted, effective cancer therapies, such as ADCs, will be needed. The increase in the average age of individuals can be explained by their adoption of healthy habits and lifestyles, which has led to greater awareness of these practices [26].
The current market status is as follows: Since the first ADC, Mylotarg® (gemtuzumab ozogamicin), was approved in 2000 by the US Food and Drug Administration (FDA), there have been 14 ADCs that received market approval so far worldwide. As of November 2022, the FDA has approved 13 different ADCs, including Lumoxiti (moxetumomab pasudotox-tdfk).
Table 1 summarizes the trade name, maker, payload design, and approved indications of these drugs [28]. Currently, there are more than 100 ADCs being developed for clinical use, with the majority intended for the treatment of cancer.
Table 1. FDA-approved ADCs as of November of 2022 [28].
ADC Drug Maker Disease Indication Payload/Payload Class Target mAb Linker Approval Year
Mirvetuximab soravtansine ImmunoGen Platinum-resistant ovarian cancer Maytansinoid DM4 FRα IgG1 / 2022
Tisotumab vedotin-tftv Seagen Inc Recurrent or metastatic cervical cancer MMAE/auristatin Tissue factor IgG1 Enzyme-cleavable 2021
Loncastuximab tesirine-lpyl ADC Therapeutics Large B-cell lymphoma SG3199/PBD dimer CD19 IgG1 Enzyme-cleavable 2021
Belantamab mafodotin-blmf GlaxoSmithKline (GSK) Adult patients with relapsed or refractory multiple myeloma MMAF/auristatin BCMA IgG1 Non-cleavable 2020, withdrawn on 22 November, 2022
Sacituzumab govitecan Immunomedics Adult patients with metastatic triple-negative breast cancer (mTNBC) who have received at least two prior therapies for patients with relapsed or refractory metastatic disease SN-38/camptothecin TROP2 IgG1 Acid-cleavable 2020
Trastuzumab deruxtecan AstraZeneca/Daiichi Sankyo Adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens DXd/camptothecin HER2 IgG1 Enzyme-cleavable 2019
Enfortumab vedotin Astellas/Seagen Genetics Adult patients with locally advanced or metastatic urothelial cancer who have received a PD-1 or PD-L1 inhibitor and a Pt-containing therapy MMAE/auristatin Nectin4 IgG1 Enzyme-cleavable 2019
Polatuzumab vedotin-piiq Genentech, Roche Relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) MMAE/auristatin CD79 IgG1 Enzyme-cleavable 2019
Moxetumomab pasudotox Astrazeneca Adults with relapsed or refractory hairy cell leukemia (HCL) PE38 (Pseudotox) CD22 IgG1 Cleavable 2018
Inotuzumab ozogamicin Pfizer/Wyeth Relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia Ozogamicin/calicheamicin CD22 IgG4 Acid-cleavable 2017
Trastuzumab emtansine Genentech, Roche HER2-positive metastatic breast cancer (mBC) following treatment with trastuzumab and a maytansinoid DM1/maytansinoid HER2 IgG1 Nnon-cleavable 2013
Brentuximab vedotin Seagen Genetics, Millennium/Takeda Relapsed HL and relapsed sALCL MMAE/auristatin CD30 IgG1 Enzyme-cleavable 2011
Gemtuzumab ozogamicin Pfizer/Wyeth Relapsed acute myelogenous leukemia (AML) Ozogamicin/calicheamicin CD33 IgG4 Acid-cleavable 2017; 2000

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15061761

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