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.
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), which we consider as an immunotoxin.
The market for ADCs is expected to continue to grow beyond 2026, as novel agents are introduced into clinical practice for several oncology indications [ 26 , 27 ].
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.
3. Nanotechnology in Medical Biotechnology
New developments are in progress to increase the selectivity as well as the efficacy of ADCs. One of hot areas of these types of developments is nanomedicines. Recognizing the importance of a comprehensive understanding of advances in pharmaceutical R&D, we felt it valuable to provide a concise overview of current developments in nanomedicines within the field of medical biotechnology when discussing the development of ADCs. Some examples of the different types of nanomedicines that are being developed and studied for various therapeutic applications can be found below. Each type of nanomedicine has unique properties and advantages that make them suitable for specific therapeutic or diagnostic purposes.
3.1. Nanoparticle-Based Drug Delivery
Nanoparticles can be used to encapsulate the drugs and deliver them to specific target sites, such as tumors or inflamed tissues. This approach can improve the efficacy and reduce the side effects of the drugs [ 29 , 30 ].
3.2. Gene Therapy
Nanoparticles can be used to deliver genetic material, such as DNA or RNA, into cells for therapeutic purposes. This approach has the potential to treat genetic disorders and some types of cancer [ 31 , 32 , 33 ].
3.3. Photodynamic Therapy
This involves using photosensitizing agents that are activated by light to kill cancer cells or bacteria. Nanoparticles can be used to deliver photosensitizers to target sites and improve the specificity of the treatment [ 32 , 34 , 35 ].
3.4. Immunotherapy
Nanoparticles can be used to deliver immunotherapeutic agents, such as antibodies or cytokines, to target sites to boost the immune system’s response against cancer or other diseases [ 32 , 36 , 37 ].
3.5. Tissue Engineering
Nanofibers and other nanomaterials can be used to create scaffolds for tissue engineering applications, such as repairing damaged tissues or organs [ 38 , 39 ].
3.6. Diagnostic Imaging
Nanoparticles can be used as contrast agents for various imaging modalities, such as positron-emission tomography (PET) [ 40 , 41 ], magnetic resonance imaging (MRI) [ 42 , 43 ], or computed tomography (CT) [ 44 ] scans, to detect and diagnose diseases.
The nanomedicine market is a rapidly growing sector that includes the development and application of nanotechnology in medicine. According to a market research report by Grand View Research, the global nanomedicine market size was valued at USD 215.0 billion in 2020 and is expected to grow at a CAGR of 13.6% from 2021 to 2028. The report suggests that the increasing prevalence of chronic diseases, such as cancer, diabetes, and cardiovascular diseases, along with the growing demand for personalized medicine, is driving the growth of the nanomedicine market. The report also highlights the rising investments in the research and development of nanomedicines, along with the increasing adoption of nanotechnology in drug delivery and diagnostic applications, as key factors contributing to the growth of the market [ 45 ].
When a drug or medical device has a therapeutic effect due to the use of nanomaterials, it is important to understand how the pharmacodynamic and pharmacokinetic responses have been affected by the size of the nanomaterial. The EUON (European Union Observatory for Nanomaterials) has a database with more than 1000 products that use nanomaterials, including 91 healthcare products, such as wound dressings, implants, and liposomal drugs for indications such as cancer, cardiovascular disease, diabetes, and infection. The US Nanomaterial Consumer Products Inventory lists 762 nanotechnology-related products in the fitness and health category, but information on the composition of the nanomaterial is missing for almost half of them.
In the pharmaceutical industry, only a small number of platform technologies are commonly used, according to submissions to the Center for Drug Evaluation and Research (CDER) of the US FDA. Some nanocrystal formulations and liposomes, considered non-biological complex drugs (NBCD), are challenging to manufacture under good manufacturing practice (GMP) conditions and require thorough physicochemical and biopharmaceutical characterization [ 46 ].
The nanomedicine market includes several segments, such as nanoscale therapeutic agents, nanodiagnostics, and nanotechnology-based medical devices. The report suggests that the nanoscale therapeutic agents segment held the largest share of the market in 2020, driven by the increasing demand for targeted drug delivery and the development of novel drug delivery systems [ 45 ].
Overall, the nanomedicine market is expected to continue its growth trajectory in the coming years, driven by advancements in nanotechnology, increasing demand for personalized medicine, and rising investments in research and development.
4. R&D of ADC Technologies
In the new class of drugs, mAbs and mimetics [ 47 , 48 ] can play a dual role. ADCs contain antibodies directly linked to a limited number of highly toxic drug warheads through a linker ( Figure 2 ). However, in the class of ACNP drugs [ 14 , 49 ], a large number of drug molecules are enclosed in a special nanocarrier. The NPDCs serve as a cargo to improve the drug concentration at the tumor site, by passive targeting mechanisms due to their enhanced permeability and retention ability. In order to overcome the limitations due to low drug concentration of the ADCs, the nanoparticle–drug combination is conjugated with the antibody ( Figure 3 ). Thus, the specificity of ACNP is improved by mAb or mimetics, and the higher cargo is provided by the NPDC. In the development process, researchers must take into account the strengths of each of the mentioned drug classes.
The mAbs that are created for the treatment of cancer use various mechanisms to fight the disease, such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and alterations in cell signaling. One well-designed drug for targeting HER2 in cancer therapy is TZM. However, clinical data show that many patients with HER2-overexpressing breast cancer do not respond to TZM-based therapies. To address this issue, a new type of biopharmaceutical drug, called ADC, is being developed. ADCs consist of an mAb as a targeting molecule, and a highly cytotoxic drug that is attached to a linker with a functional group, which is then connected to the Lys amine group and Cys thiol group of the mAb [ 50 ]. The primary advantage of ADCs is that the cytotoxic drug is specifically delivered to the tumor cell, increasing the efficacy and reducing the side effects due to their limited off-target toxicity [ 51 ].
Recently, several drug-loaded nanoparticles have been in development for conjugation with mAb, e.g., functionalized magnetic nanoparticles [ 52 ], including trastuzumab-modified gold nanoparticles [ 53 ], as potential multimodal agents. It was found that these nanoparticles bind with high specificity to the HER2+ cell lines but not to the HER2- cell lines. Biopolymer-based as well as poly(lactide-co-glycolide) (PLGA) nanocarriers were loaded with the oxalilplatin chemotherapeutic drug and coated with mAb [ 54 ]. There is a study which demonstrated that the anti-cancer drug loaded in polymeric micelles or cyclodextrins improved the stability and the solubility of the prodrug, which was then connected to mAb, resulting in high efficacy [ 55 ].
Recent strategies for developing new ADCs involve selecting new components for targeting.
mAb selection: For targeting, biologics, such as mAbs, fragments, and other backbones (e.g., single-chain variable fragment (scFv), affibody, Pentarin, and antibody–cytokine fusion proteins), are used to target HER2 or other antigens. Generally, lysines with free amines are more common than cysteines with disulfides and are not evenly distributed in the antibody [ 56 , 57 ]. However, Genentech is currently testing modified antibodies with engineered cysteines. Antibody mimetics are also the focus of recent research due to their importance. The site specificity/efficacy of the composed drug can be improved by adding a new building block as an antibody mimetic, e.g., single domain antibody [ 58 ], nanobody [ 59 ], or affibody [ 60 ].
Toxins: There are numerous cytotoxic drugs that can be used as payloads, such as Maytansine (DM1, DM4), Auristatine (MMAE), SN-38, Doxorubicin, and Duocarmycin analogues [ 61 ].
Linker selection: Linkers have a crucial role in the ADC and ACNP constructions, respectively. This part of the construction is responsible for the stability of cargo. The linker must be stable during the circulation in the bloodstream to avoid the leakage of drug molecules. A class of linkers is designed according to bio-orthogonal chemistry [ 62 ], which allows cleavage in the microenvironment of cancer cells [ 63 ]. Linkers can be either cleavable or non-cleavable, with various types of cleavable linkers, such as chemically labile linkers and enzyme-cleavable linkers (e.g., pH-sensitive linkers, disulfide linkers, peptide linkers, β-glucuronide linkers, and aldehyde tags [ 64 ]). Examples of linker platforms include the ImmunoGen Platform, Val-Cit, Disulphide, and Hydrazon [ 65 ]. For the nondegradable linkers, the connection of the cytotoxic and the antibody is non-sensitive to proteolytic degradation [ 66 ].
In the construction of ADCs, the biomolecule antibody requires precise chemical modification under specific conditions, and the payload capacity is relatively limited. In contrast, the formation of the nanoparticle drug constructs can occur in a less sensitive environment. In the final step of the ACNP formation, the activity of the antibody can be better protected.
There are many developments focusing on how to modify the TZM antibody. In this section, we describe a few steps of a synthesis project for creating a modified version of the trastuzumab antibody as an example. As a first step, lysine residues on the antibody are chosen as the conjugation sites to avoid disturbing the antibody’s structure and function and to maintain its favorable pharmacokinetic properties. Secondly, toxins are selected on the basis of their functional groups, and linkers are chosen for their ability to bind the toxin to the biopolymer and the NPDC to the mAb. Finally, biopolymers are selected on the basis of their solubility in water, ability to self-assemble into nanoparticles of a desired size and distribution, and their functional and steric properties for connection to the mAb.
A new approach to combining mAbs with toxic drugs involves using a biopolymer-based nanoparticle. This type of ADC is composed of a biodegradable biopolymer nanoparticle that contains a highly cytotoxic payload and is decorated with the targeting TZM antibody on the surface. The synthetic route for creating this ADC begins with the creation of a drug/toxin biopolymer conjugate that is coupled through a spacer (PDC). The biopolymer (Poly_1) is capable of self-assembling, and by adding Biopolymer_2 (Poly_2), a nanoparticle containing the drug molecule is obtained (NPDC). The functional groups of NPDC are then modified with a maleimide-containing linker (e.g., SMCC) that can react with lysine groups of the TZM antibody.
This proposed method has potential advantages over other ADCs because the NPDC can be precisely prefabricated [ 67 , 68 ], and in the final step, it can be conjugated to the mAb, resulting in the appropriate ACNP ( Figure 3 ). It is suspected that these constructions have the benefits of highly targeting cancer cells due to their antibody content, as well as a high efficacy due to the high payload carried by the conjugated nanoparticles.
This new structure will allow for a combination of immune and chemotherapeutic nanomedicine, resulting in overall higher anticancer efficacy.
For the class of antibody-functionalized lipid-based nanoparticles or solid–liquid particles, in the first step, different terminal groups, such as amino, carboxyl, maleimide, or NHS, are formed [ 69 ], then they are conjugated with the appropriate mAb.
New elements, such as nanoparticles (e.g., dendrimers, PLGA, and polymer-based ADCs), are being explored in ADC development. The Mersena (MA) technology uses a polyacetal polymer-based platform for creating ADCs.
In the field of ADCs, the technology of “cleavable linker” currently has the largest and most robust market share. Cleavable linkers are advantageous because they offer more varied applications compared with non-cleavable linkers due to their ability to use different mechanisms to act on disease sites. In May 2022, Aptamer and PinotBio entered into a collaborative effort to develop Optimer-drug conjugates as an alternative format for ADCs to target four specific non-blood-based cancer targets, namely Nectin-4, Tissue Factor, CEACAM5, and CD73. These biomarkers have the potential to target solid tumors, which have a poor response to chemotherapy. This could lead to the development of therapeutics with a smaller size that would allow for greater penetration of the tumor compared with standard antibody-based ADCs [ 70 , 71 ].
In terms of applications, “Breast Cancer” has the highest market share for ADCs. The number of breast cancer cases has increased dramatically over the years, with the World Health Organization reporting nearly 19.3 million cases in 2020, almost doubled from the 10 million cases reported in 2000. This increase in breast cancer cases has made it the most prevalent form of cancer, surpassing lung cancer. Consequently, ADCs are being used as a viable treatment option, which has increased the market size for ADCs.
Geographically, “North America” holds the largest market share for ADCs. Most of the development in the field of ADCs is conducted in North America, including research and development and clinical trials. The presence of major pharmaceutical companies based in the United States, such as Johnson & Johnson, Pfizer, Gilead Sciences, and Abbott International, has significantly contributed to the revenue share of the region. The American Cancer Society has predicted 1.9 million cancer cases and 609,000 deaths in the region in 2022, which is likely to boost the market for ADCs [ 26 ].
Some recent development examples in the market are mentioned below. In June 2022, ADC Therapeutics was in the process of adding its second ADC to the company’s product portfolio, with the introduction of camidanlumab tesirine. This drug has shown promising results in Phase 2 of clinical trials, and the company is likely to seek approval from the US Food and Drug Administration (FDA) to use it as a treatment option for Hodgkin’s lymphoma [ 72 ].
Also in June 2022, Spirea Limited announced that it had received GBP 2.4 million in funding from investors to develop highly specialized ADCs for treating solid tumors. Their technology allows for a higher drug-to-antibody ratio, which means that more of the drug can be delivered to the affected area to eliminate cancer cells. This could lead to more effective cancer treatments [ 73 ].
In May 2022, the FDA approved the use of fam-trastuzumab deruxtecan-nxki (Enhertu ® ) for the treatment of metastatic HER2-positive breast cancer. The drug was developed by Daiichi Sankyo and AstraZeneca [ 74 ].
5. Challenges and Business Risks in R&D of ADCs
5.1. Risks for R&D, Limits, and Failures
For more than 100 years, the concept of ADCs has existed, but there are still only a limited number of varieties available on the market. Most of the varieties under research are still in the early stages of development. The main reason for this is that the development of ADC drugs is a challenging process, with high technical barriers. ADC drugs require multiple steps to become effective after entering the body, and each step presents significant technical difficulties that must be overcome.
The primary ethical concern regarding medical science and technology is often the potential risk involved, especially for new and unfamiliar technologies. While risk and risk–benefit analyses are only one aspect of ethical oversight, they are often used interchangeably in ethical review and risk assessment. This is because both the Common Rule and FDA emphasize the importance of minimizing risk for human subjects and require the local Institutional Review Boards (IRBs) to consider the risk–benefit analysis when making decisions about proposed research. In the case of ADCs, toxicological analyses are typically the first thing that comes to mind when assessing risk, as they are critical for evaluating the safety of these molecules. There is a significant body of literature on toxicological risk analysis for ADCs, and many new methodologies have been developed and published [ 75 , 76 , 77 ]. However, business risk methodologies for the development of these molecules have been less discussed. Developing an ADC involves significant technological challenges and a complex development process that can be very expensive. Therefore, the business risk associated with developing an ADC is very high.
In general, the high rates of drug development failures can be attributed to various reasons, including: Unreliable published data; Biopharmaceutical issues, such as suboptimal pharmacokinetics; Poorly predictive preclinical models used in discovery research and preclinical testing; The concept of target-based drug discovery, which involves complex target selection, competition for proprietary targets, and the validation process; Complexities of clinical trials, particularly in treating chronic diseases, along with increasing demands from regulatory authorities and payers.
Smaller organizations lacking the know-how and resources of larger organizations, leading to lower probability of technical and regulatory success from Phase I to submission [ 78 , 79 ].
While ADCs hold great promise for the treatment of cancer and other diseases, there are several challenges and business risks associated with their development. Some of these challenges and risks include: Complex Manufacturing: ADCs are complex molecules that require precise conjugation of the antibody and the cytotoxic agent. The manufacturing process can be challenging and time-consuming, and any variability in the manufacturing process can affect the quality and efficacy of the final product. Regulatory Challenges: ADCs are subject to strict regulatory oversight, and the approval process can be lengthy and expensive. Regulators require extensive data on the safety and efficacy of ADCs, including data on the pharmacokinetics, pharmacodynamics, and toxicology of the drug. Target Selection: Choosing the right target for an ADC is critical for its success. If the target is not expressed on the tumor cells, or if it is expressed on normal cells, the ADC may not be effective or may cause off-target toxicity [ 80 , 81 , 82 ]. Resistance: As with any cancer therapy, the development of resistance is a significant challenge for ADCs. Cancer cells can develop resistance to the antibody, the cytotoxic agent, or both, rendering the ADC ineffective. Intellectual Property: ADC development involves complex intellectual property issues, including patenting of the antibody, the linker, and the cytotoxic agent. Companies must navigate these issues carefully to avoid infringement and protect their intellectual property. Cost: Developing ADCs can be extremely expensive, with high costs associated with manufacturing, clinical trials, and regulatory approval. There is also significant competition in the market, which can drive down prices and limit profitability.
The characterization of nanotechnology-related products requires a combination of different techniques to understand their physicochemical features and how these impact efficacy and product safety. From a regulatory standpoint, assessment of the environmental toxicity and effects on occupational health are required for the raw materials (excipients), while drug products and medical devices follow their own framework, with a greater emphasis on the therapeutic applications [ 83 ].
Pharmaceutical companies are currently facing significant barriers to entering the emerging nanomedicine market, with recent trends in the European regulatory landscape indicating increased restrictions and a narrower field of competitors. However, a growing knowledge base and a rising number of drug products and medical devices in the market offer new opportunities for the industry [ 83 ].
The European Medicines Agency (EMA) has established a framework for evaluating nanomedicines, which includes the following principles: The evaluation of any nanomedicine should be based on established principles of benefit/risk analysis, rather than solely on the basis of the technology itself (including the use of Risk Management Plans and Environmental Risk Assessment) [ 77 , 83 ]. Specialized multidisciplinary expertise is required, with a group of mixed academia and regulatory experts pooling their knowledge of quality, safety, and kinetics to support evaluation and formulate guidelines [ 83 ]. Close cooperation with other scientific committees (such as the Scientific Committee on Emerging and Newly Identified Health Risks and the European Food Safety Authority), networks (such as the Nanotechnology Knowledge Base and the European Technology Platform for Nanomedicine), and the European Commission [ 83 ]. International cooperation, with EMA chairing an international expert group that includes the US FDA, Japan MHLW, Health Canada, and TGA Australia. Transparent dialogue with stakeholders [ 83 , 84 ].
5.2. Case Studies
In 2012, the FDA approvals were reviewed, and the most probable reasons for failures in Phase II and Phase III clinical development were found to be lack of efficacy (56%), safety issues (28%), changing strategies (7%), commercial reasons (5%), and operational challenges (5%). These results were confirmed by a second analysis of 142 drug R&D projects of AstraZeneca, which found that preclinical and Phase I projects failed primarily failed due to safety reasons, whereas projects failing in Phases II and III commonly lacked efficacy [ 78 ].
In the pharmaceutical research and development (R&D) process, discovery research takes 4.5 years, preclinical testing lasts for 1 year, and the three clinical development phases require 1.5, 2.5, and 2.5 years, respectively, with an additional 18 months from submission to launch. Basic research and post-approval Phase IV trials must also be considered in the overall R&D time. There are two additional findings when reviewing drug R&D timelines. First, clinical development takes longer than in the past. Second, the average time for FDA review and approval has decreased significantly since the Prescription Drug User Fee Act (PDUFA) was enacted, potentially due to fast-track status or accelerated approvals.
The long overall time of pharmaceutical R&D impacts on total R&D costs increases the risk of industry competition and raises the uncertainty of generic competition. This is due to the capitalization of R&D costs, which increases overall expenditures, the risk of competition, which reduces the chance to be first-to-market, and the commercial success of a drug candidate. Additionally, the effective date of generic competition can influence the ROI of a new drug by reducing the commercially usable patent term.
At present, the duration of the clinical trials is longer due to the COVID-19 pandemic because there are many vaccine candidates in development which are requiring many resources [ 78 ].
The biotechnology industry faces the challenge of covering the entire R&D process and clinical costs within a limited timeframe, typically no more than 10 years and sometimes as little as 5 years. To address this challenge, many companies are exploring ways to shorten the development process. One approach is to use open innovation, which involves collaborating with external partners and outsourcing R&D activities instead of relying solely on in-house resources. By leveraging the expertise of external partners, companies can avoid the time and cost of developing new skills internally. This strategy can help accelerate the development process and potentially reduce costs. All of the following factors can contribute to a decrease in R&D efficiency in the pharmaceutical industry. An inadequate number of projects in early R&D phases can lead to a lack of diversity in a company’s pipeline and limit the potential for new drug discoveries. More technically complex research for new drug targets and subsequent preclinical and clinical studies can increase the time and resources required for R&D, which can negatively impact efficiency.
The burden for approval and reimbursement of new molecular entities (NMEs) can also be high, particularly in view of the already-approved drugs in the market. This can lead to a more risk-averse approach from both regulators and society, which may result in longer approval timelines and a lower likelihood of success for new drugs.
Mergers and acquisitions (M&As) can have a negative effect on R&D efficiency as well, particularly if the integration of the two companies results in the duplication of efforts and resources. Similarly, the decreasing number of research-based pharmaceutical companies taking the financial risk of drug R&D can limit competition and innovation in the industry.
Licensing, co-development, or joint ventures can have a negative effect on clinical development and approval durations if there are disagreements or delays in decision-making and resource allocation between the partnering companies. Overall, a combination of these factors can contribute to the challenges facing the pharmaceutical industry in maintaining R&D efficiency and productivity [ 78 ].
5.3. New Forms for R&D
It is encouraging to see that more pharmaceutical companies are recognizing the need to make changes to their R&D ecosystems in order to improve their R&D efficiencies. The process changes that these companies are making can help them to manage better their R&D activities and reduce costs while also expanding their competence and technology base and strengthening their innovation potential.
One way that companies are creating growth options is through M&As, which can provide access to new technologies and pipelines and expand their market reach [ 85 ]. Restructuring R&D into smaller, more manageable units, similar to those found in biotechnology companies, can also help to improve the efficiency and focus on specific therapeutic areas or technologies.
Outsourcing and virtual R&D are increasingly being used by pharmaceutical companies to reduce R&D costs, particularly in areas such as preclinical and clinical development, where third-party service providers can provide cost-efficient solutions. Companies are also widening their competence field by expanding collaborations and research partnerships, which can provide access to new technologies, scientific expertise, and drug candidates in all phases of development.
Venture capital investments are being used to strengthen innovation potential, particularly in the area of early-stage drug discovery, where startups and emerging companies are developing new technologies and drug candidates. Lastly, some companies are using the power of the crowd to broaden their knowledge base, for example, by crowdsourcing ideas and solutions through open innovation platforms.
Overall, the process changes being made by pharmaceutical companies reflect a recognition of the need to adapt to the changing landscape of R&D and to adopt more agile, innovative approaches to improve R&D efficiencies and productivity [ 78 ].
The concept of Open Innovation has garnered increasing interest in the past 20 years, particularly since Henry Chesbrough introduced the term in 2003, which led to the development of a new field of knowledge. However, despite the extensive research, there is no standardized, all-encompassing theory of Open Innovation. Instead, there exists a range of models that address different aspects and are applicable to specific contexts and industries. One of the industries that has adopted Open Innovation is the pharmaceutical industry. The pharmaceutical industry’s move towards Open Innovation has unique features, such as the need to address the current productivity crisis as a driver for change and the R&D-intensive nature of the industry [ 86 ].
Due to the high complexity of the biopharmaceutical industry, outsourcing, “slicing up” of tasks, and collaboration with other companies are more likely to occur. Another characteristic of the sector is that the development and production of a biologically active ingredient involves thousands of steps, resulting in a long value chain. At almost every step, management must decide whether to keep the given activity in-house or to outsource it.
In modern biotechnology projects and programs, there is a trend towards project network organizations (PNOs) as opposed to project-based firms (PBFs), which have become increasingly important contexts for interorganizational project cooperation. Due to organizational specialization, PNOs have become general organizational forms that combine the coordination ability of PBFs with the resource richness of networks. PNOs connect legally independent but often operationally interdependent individuals and organizations in the form of strategically coordinated project teams and flexible partner groups that persist beyond individual projects. On the basis of empirical review, PNOs have outstanding characteristics in complex product and system development, research, open innovation, and international development. Differences between the two structures can be related to the variety and connectivity of the projects, the degree of specialization, and the geographical concentration of the resources [ 87 ].
6. Conclusions
A review of social research in the healthcare industry suggests that there will be a significant demand for effective oncology solutions in the near future, indicating a vast potential market and high risks for medical biotechnology, including ADCs. Market analyses, forecasts, and acquisitions clearly demonstrate this potential. We are on the cusp of a major breakthrough, with only 14 approved ADC products and more than 100 in clinical trials, a number that is set to increase rapidly. Regulatory and clinical acceptance for ADCs is also improving. However, there are technological challenges that make the situation difficult, which could be addressed by the NPDC route as a technological option.
Given the recent excitement surrounding the potential of artificial intelligence (AI) in drug discovery and development, particularly driven by advancements in machine learning and its role in the competitive race for the next blockbuster drug, it is expected that pharmaceutical companies will leverage these computer-based platforms for the development of the next-generation ADCs [ 88 ].
Moreover, the potential of ADCs as a therapeutic strategy extends beyond cancer and is substantial. Research is already being conducted on the use of ADCs for the treatment of non-oncological conditions, such as autoimmune and cardiovascular diseases, diabetes, and antimicrobial infections [ 89 ].
Since biopharma R&D is highly capital-intensive, it is crucial to identify business risks as early as possible and minimize them where possible. New development principles, such as open innovation, new assembly structures, and new structures for collaboration, offer an opportunity to achieve this.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Author Contributions
Conceptualization, B.K. and J.B.; methodology, B.K. and J.B.; software, B.K.; validation, B.K.; formal analysis, B.K.; investigation, B.K. and J.B.; resources, B.K. and J.B.; data curation, B.K. and J.B.; writing—original draft preparation, B.K. and J.B.; writing—review and editing, B.K.; visualization, B.K.; supervision, B.K. and J.B.; project administration, J.B. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
Abbreviations
References
1. Fernald K.D.S. Pennings H.P.G. Bosch J.F.V.D. Commandeur H.R. Claassen E. The moderating role of absorptive capacity and the differential effects of acquisitions and alliances on Big Pharma firms’ innovation performance PLoS ONE 2017 12 e0172488 10.1371/journal.pone.0172488 28231332 PMC5322930
2. Bayer ADC Fails Pivotal Mesothelioma Trial Available online: https://www.fiercebiotech.com/biotech/bayer-adc-fails-pivotal-mesothelioma-trial (accessed on 24 July 2017)
3. Pfizer Invests $43 Billion to Battle Cancer Available online: https://www.pfizer.com/news/press-release/press-release-detail/pfizer-invests-43-billion-battle-cancer (accessed on 13 March 2023)
4. With $43B Buyout, Pfizer Sees Cancer Specialist Seagen as a ‘Goose’ Laying ‘Golden Eggs’ Available online: https://www.fiercepharma.com/pharma/43b-buyout-pfizer-sees-seagen-its-golden-goose (accessed on 13 March 2023)
5. After Dose De-Escalation, Death Drives Magenta to Pause Antibody-Drug Conjugate Leukemia Trial Available online: https://www.fiercebiotech.com/biotech/after-dose-de-escalation-death-drives-magenta-pause-antibody-drug-conjugate-leukemia-trial (accessed on 26 January 2023)
6. Zolot R.S. Basu S. Million R.P. Antibody–drug conjugates Nat. Rev. Drug Discov. 2013 12 259 260 10.1038/nrd3980 23535930
7. Kapinos K.A. Hu E. Trivedi J. Geethakumari P.R. Kansagra A. Cost-Effectiveness Analysis of CAR T-Cell Therapies vs Antibody Drug Conjugates for Patients with Advanced Multiple Myeloma Cancer Control. 2023 30 10732748221142945 10.1177/10732748221142945 36651055 PMC9869188
8. Mckertish C.M. Kayser V. Advances and Limitations of Antibody Drug Conjugates for Cancer Biomedicines 2021 9 872 10.3390/biomedicines9080872 34440076 PMC8389690
9. Wu M. Huang W. Yang N. Liu Y. Learn from antibody–drug conjugates: Consideration in the future construction of peptide-drug conjugates for cancer therapy Exp. Hematol. Oncol. 2022 11 93 10.1186/s40164-022-00347-1 36348391 PMC9644565
10. Espelin C.W. Leonard S.C. Geretti E. Wickham T.J. Hendriks B.S. Dual HER2 Targeting with Trastuzumab and Liposomal-Encapsulated Doxorubicin (MM-302) Demonstrates Synergistic Antitumor Activity in Breast and Gastric Cancer Cancer Res. 2016 76 1517 1527 10.1158/0008-5472.CAN-15-1518 26759238
11. Hu X. Kwon N. Yan K. Sedgwick A.C. Chen G. He X. James T.D. Yoon J. Bio-Conjugated Advanced Materials for Targeted Disease Theranostics Adv. Funct. Mater. 2020 30 1907906 10.1002/adfm.201907906
12. Rodallec A. Franco C. Robert S. Sicard G. Giacometti S. Lacarelle B. Bouquet F. Savina A. Lacroix R. Dignat-George F. Prototyping Trastuzumab Docetaxel Immunoliposomes with a New FCM-Based Method to Quantify Optimal Antibody Density on Nanoparticles Sci. Rep. 2020 10 4147 10.1038/s41598-020-60856-z 32139753 PMC7057981
13. Matusewicz L. Filip-Psurska B. Psurski M. Tabaczar S. Podkalicka J. Wietrzyk J. Ziółkowski P. Czogalla A. Sikorski A.F. EGFR-targeted immunoliposomes as a selective delivery system of simvastatin, with potential use in treatment of triple-negative breast cancers Int. J. Pharm. 2019 569 118605 10.1016/j.ijpharm.2019.118605 31400433
14. Juan A. Cimas F.J. Bravo I. Pandiella A. Ocaña A. Alonso-Moreno C. Antibody Conjugation of Nanoparticles as Therapeutics for Breast Cancer Treatment Int. J. Mol. Sci. 2020 21 6018 10.3390/ijms21176018 32825618 PMC7504566
15. Kasenda B. König D. Manni M. Ritschard R. Duthaler U. Bartoszek E. Bärenwaldt A. Deuster S. Hutter G. Cordier D. Targeting immunoliposomes to EGFR-positive glioblastoma ESMO Open 2022 7 100365 10.1016/j.esmoop.2021.100365 34998092 PMC8741448
16. Mamot C. Wicki A. Hasler-Strub U. Riniker S. Li Q. Holer L. Bärtschi D. Zaman K. von Moos R. Dedes K.J. A multicenter phase II trial of anti-EGFR-immunoliposomes loaded with doxorubicin in patients with advanced triple negative breast cancer Sci. Rep. 2023 13 3705 10.1038/s41598-023-30950-z 36879012 PMC9988854
17. Kumar A. Lale S.V. Alex M.A. Choudhary V. Koul V. Folic Acid and Trastuzumab Conjugated Redox Responsive Random Multiblock Copolymeric Nanocarriers for Breast Cancer Therapy: In-Vitro and in-Vivo Studies Colloids Surf. B Biointerfaces 2017 149 369 378 10.1016/j.colsurfb.2016.10.044 27846450
18. Peng J. Chen J. Xie F. Bao W. Xu H. Wang H. Xu Y. Du Z. Herceptin-Conjugated Paclitaxel Loaded PCL-PEG Worm-like Nanocrystal Micelles for the Combinatorial Treatment of HER2-Positive Breast Cancer Biomaterials 2019 222 119420 10.1016/j.biomaterials.2019.119420 31445322
19. Kolahkaj F.F. Derakhshandeh K. Khaleseh F. Azandaryani A.H. Mansouri K. Khazaei M. Active Targeting Carrier for Breast Cancer Treatment: Monoclonal Antibody Conjugated Epirubicin Loaded Nanoparticle J. Drug Deliv. Sci. Technol. 2019 53 101136 10.1016/j.jddst.2019.101136
20. Wang Y. Qian J. Yang M. Xu W. Wang J. Hou G. Ji L. Suo A. Doxorubicin/Cisplatin Co-Loaded Hyaluronic Acid/Chitosan-Based Nanoparticles for in Vitro Synergistic Combination Chemotherapy of Breast Cancer Carbohydr. Polym. 2019 225 115206 10.1016/j.carbpol.2019.115206 31521263
21. Zhong S. Ling Z. Zhou Z. He J. Ran H. Wang Z. Zhang Q. Song W. Zhang Y. Luo J. Herceptin-Decorated Paclitaxel-Loaded Poly(Lactide-Co-Glycolide) Nanobubbles: Ultrasound-Facilitated Release and Targeted Accumulation in Breast Cancers Pharm. Dev. Technol. 2020 25 454 463 10.1080/10837450.2019.1709500 31873051
22. Pilkington G.A. Pedersen J.S. Briscoe W.H. Dendrimer nanofluids in the concentrated regime: From polymer melts to soft spheres Langmuir 2015 31 3333 3342 10.1021/la504870f 25723405
23. Choi J.-H. Gu H.-J. Park K.-H. Hwang D.-S. Kim G.-C. Anti-Cancer Activity of the Combinational Treatment of Noozone Cold Plasma with p-FAK Antibody-Conjugated Gold Nanoparticles in OSCC Xenograft Mice Biomedicines 2022 10 2259 10.3390/biomedicines10092259 36140360 PMC9496586
24. Lodhi M.S. Khalid F. Khan M.T. Samra Z.Q. Muhammad S. Zhang Y.-J. Mou K. A Novel Method of Magnetic Nanoparticles Functionalized with Anti-Folate Receptor Antibody and Methotrexate for Antibody Mediated Targeted Drug Delivery Molecules 2022 27 261 10.3390/molecules27010261 35011493 PMC8747068
25. Wilcock P. Webster R.M. The breast cancer drug market Nat. Rev. Drug Discov. 2021 20 339 340 10.1038/d41573-021-00018-6 33483705
26. Antibody Drug Conjugate Market, a $13.15 billion Industry by 2030 with a CAGR of 14.12% 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)
27. Pazo C.D. Nawaz K. Webster R.M. The oncology market for antibody–drug conjugates Nat. Rev. Drug Discov. 2021 20 583 584 10.1038/d41573-021-00054-2 33762691
28. Antibody-Drug Conjugates (ADCs) List Approved by FDA (2000–2023) Available online: https://axispharm.com/antibody-drug-conjugatesadcs-list-approved-by-fda2000-2022/ (accessed on 27 December 2022)
29. Mitchell M.J. Billingsley M.M. Haley R.M. Wechsler M.E. Peppas N.A. Langer R. Engineering precision nanoparticles for drug delivery Nat. Rev. Drug Discov. 2020 20 101 124 10.1038/s41573-020-0090-8 33277608 PMC7717100
30. Afzal O. Altamimi A.S.A. Nadeem M.S. Alzarea S.I. Almalki W.H. Tariq A. Mubeen B. Murtaza B.N. Iftikhar S. Riaz N. Nanoparticles in Drug Delivery: From History to Therapeutic Applications Nanomaterials 2022 12 4494 10.3390/nano12244494 36558344 PMC9781272
31. Roma-Rodrigues C. Rivas-García L. Baptista P.V. Fernandes A.R. Gene Therapy in Cancer Treatment: Why Go Nano? Pharmaceutics 2020 12 233 10.3390/pharmaceutics12030233 32151052 PMC7150812
32. Mosleh-Shirazi S. Abbasi M. Moaddeli M.R. Vaez A. Shafiee M. Kasaee S.R. Amani A.M. Hatam S. Nanotechnology Advances in the Detection and Treatment of Cancer: An Overview Nanotheranostics 2022 6 400 423 10.7150/ntno.74613 36051855 PMC9428923
33. Nakamura T. Yamada Y. Sato Y. Khalil I.A. Harashima H. Innovative nanotechnologies for enhancing nucleic acids/gene therapy: Controlling intracellular trafficking to targeted biodistribution Biomaterials 2019 218 119329 10.1016/j.biomaterials.2019.119329 31306827
34. Chizenga E.P. Abrahamse H. Nanotechnology in Modern Photodynamic Therapy of Cancer: A Review of Cellular Resistance Patterns Affecting the Therapeutic Response Pharmaceutics 2020 12 632 10.3390/pharmaceutics12070632 32640564 PMC7407821
35. Hu D. Pan M. Yu Y. Sun A. Shi K. Qu Y. Qian Z. Application of nanotechnology for enhancing photodynamic therapy via ameliorating, neglecting, or exploiting tumor hypoxia View 2020 1 e6 10.1002/viw2.6
36. Goldberg M.S. Improving cancer immunotherapy through nanotechnology Nat. Rev. Cancer 2019 19 587 602 10.1038/s41568-019-0186-9 31492927
37. Akkın S. Varan G. Bilensoy E. A Review on Cancer Immunotherapy and Applications of Nanotechnology to Chemoimmunotherapy of Different Cancers Molecules 2021 26 3382 10.3390/molecules26113382 34205019 PMC8199882
38. Deng C. Xu C. Zhou Q. Cheng Y. Advances of nanotechnology in osteochondral regeneration WIREs Nanomed. Nanobiotechnol. 2019 11 e1576 10.1002/wnan.1576 31329375
39. Kumar R. Aadil K.R. Ranjan S. Kumar V.B. Advances in nanotechnology and nanomaterials based strategies for neural tissue engineering J. Drug Deliv. Sci. Technol. 2020 57 101617 10.1016/j.jddst.2020.101617
40. Körhegyi Z. Rózsa D. Hajdu I. Bodnár M. Kertész I. Kerekes K. Kun S. Kollár J. Varga J. Garai I. Synthesis of 68 Ga-Labeled Biopolymer-based Nanoparticle Imaging Agents for Positron-emission Tomography Anticancer Res. 2019 39 2415 2427 10.21873/anticanres.13359 31092434
41. Szabó J.P. Csige K. Kálmán-Szabó I. Arató V. Opposits G. Jószai I. Kertész I. Képes Z. Méhes G. Fenyvesi F. In vivo assessment of tumor targeting potential of 68Ga-labelled randomly methylated beta-cyclodextrin (RAMEB) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) using positron emission tomography Int. J. Pharm. 2023 630 122462 10.1016/j.ijpharm.2022.122462 36462739
42. Hajdu I. Trencsényi G. Bodnár M. Emri M. Bánfalvi G. Sikula J. Márián T. Kollár J. Vámosi G. Borbély J. Tumor-specific Localization of Self-assembled Nanoparticle PET/MR Modalities Anticancer Res. 2014 34 49 59 24403444
43. Pallares R.M. Mottaghy F.M. Schulz V. Kiessling F. Lammers T. Nanoparticle diagnostics and theranostics in the clinic J. Nucl. Med. 2022 63 1802 1808 10.2967/jnumed.122.263895 36302654 PMC9730918
44. Luo D. Wang X. Burda C. Basilion J.P. Recent development of gold nanoparticles as contrast agents for cancer diagnosis Cancers 2021 13 1825 10.3390/cancers13081825 33920453 PMC8069007
45. Grand View Research Nanomedicine Market Size, Share & Trends Analysis Report by Product (Therapeutics, Diagnostics), by Application (Oncology, Infectious Diseases), by Region, and Segment Forecasts, 2021–2028. Report ID: 978-1-68038-942-5 2021 Available online: https://www.grandviewresearch.com/industry-analysis/nanomedicine-market (accessed on 13 March 2023)
46. Marques M.R. Choo Q. Ashtikar M. Rocha T.C. Bremer-Hoffmann S. Wacker M.G. Nanomedicines—Tiny particles and big challenges Adv. Drug Deliv. Rev. 2019 151–152 23 43 10.1016/j.addr.2019.06.003 31226397
47. Whaby M. Khan I. O’Bryan J.P. Chapter Eight—Targeting The “Undruggable” RAS with Biologics Advances in Cancer Research Academic Press Cambridge, MA, USA 2022 Volume 153 237 266 10.1016/bs.acr.2021.07.006 9780128244852 0065-230X PMC9627686 35101232
48. Singh K. Canakci M. Kanjilal P. Williams N. Shanthalingam S. Osborne B.A. Thayumanavan S. Evaluation of Cellular Targeting by Fab′ vs Full-Length Antibodies in Antibody–Nanoparticle Conjugates (ANCs) Using CD4 T-cells Bioconjugate Chem. 2022 33 486 495 1043-1802 10.1021/acs.bioconjchem.2c00024 PMC9254259 35139308
49. Johnston M.C. Scott C.J. Antibody conjugated nanoparticles as a novel form of antibody drug conjugate chemotherapy Drug Discov. Today Technol. 2018 30 63 69 10.1016/j.ddtec.2018.10.003 30553522
50. Abdollahpour-Alitappeh M. Lotfinia M. Gharibi T. Mardaneh J. Farhadihosseinabadi B. Larki P. Faghfourian B. Sepehr K.S. Abbaszadeh-Goudarzi K. Johari B. Antibody–drug conjugates (ADCs) for cancer therapy: Strategies, challenges, and successes J. Cell. Physiol. 2018 234 5628 5642 10.1002/jcp.27419 30478951
51. Kang M.S. Kong T.W.S. Khoo J.Y.X. Loh T.-P. Recent developments in chemical conjugation strategies targeting native amino acids in proteins and their applications in antibody–drug conjugates Chem. Sci. 2021 12 13613 13647 10.1039/D1SC02973H 34760149 PMC8549674
52. Oltolina F. Colangelo D. Miletto I. Clemente N. Miola M. Verné E. Prat M. Follenzi A. Tumor Targeting by Monoclonal Antibody Functionalized Magnetic Nanoparticles Nanomaterials 2019 9 1575 10.3390/nano9111575 31698869 PMC6915337
53. Żelechowska-Matysiak K. Wawrowicz K. Wierzbicki M. Budlewski T. Bilewicz A. Majkowska-Pilip A. Doxorubicin- and Trastuzumab-Modified Gold Nanoparticles as Potential Multimodal Agents for Targeted Therapy of HER2+ Cancers Molecules 2023 28 2451 10.3390/molecules28062451 36985421 PMC10058186
54. Zumaya A.L.V. Rimpelová S. Štějdířová M. Ulbrich P. Vilčáková J. Hassouna F. Antibody Conjugated PLGA Nanocarriers and Superparmagnetic Nanoparticles for Targeted Delivery of Oxaliplatin to Cells from Colorectal Carcinoma Int. J. Mol. Sci. 2022 23 1200 10.3390/ijms23031200 35163122 PMC8835878
55. Ioele G. Chieffallo M. Occhiuzzi M.A. De Luca M. Garofalo A. Ragno G. Grande F. Anticancer Drugs: Recent Strategies to Improve Stability Profile, Pharmacokinetic and Pharmacodynamic Properties Molecules 2022 27 5436 10.3390/molecules27175436 36080203 PMC9457551
56. Khongorzul P. Ling C.J. Khan F.U. Ihsan A.U. Zhang J. Antibody–Drug Conjugates: A Comprehensive Review Mol. Cancer Res. 2020 18 3 19 10.1158/1541-7786.MCR-19-0582 31659006
57. Hasan M. Laws M. Jin P. Rahman K.M. Factors influencing the choice of monoclonal antibodies for antibody–drug conjugates Drug Discov. Today 2021 27 354 361 10.1016/j.drudis.2021.09.015 34597756
58. Nessler I. Khera E. Vance S. Kopp A. Qiu Q. Keating T.A. Abu-Yousif A.O. Sandal T. Legg J. Thompson L. Increased Tumor Penetration of Single-Domain Antibody–Drug Conjugates Improves In Vivo Efficacy in Prostate Cancer Models Cancer Res. 2020 80 1268 1278 10.1158/0008-5472.CAN-19-2295 31941698 PMC7073300
59. Salvador J.-P. Vilaplana L. Marco M.-P. Nanobody: Outstanding features for diagnostic and therapeutic applications Anal. Bioanal. Chem. 2019 411 1703 1713 10.1007/s00216-019-01633-4 30734854
60. Ståhl S. Gräslund T. Eriksson Karlström A. Frejd F.Y. Nygren P.Å. Löfblom J. Affibody Molecules in Biotechno-logical and Medical Applications Trends Biotechnol. 2017 35 691 712 10.1016/j.tibtech.2017.04.007 28514998
61. Conilh L. Sadilkova L. Viricel W. Dumontet C. Payload diversification: A key step in the development of antibody–drug conjugates J. Hematol. Oncol. 2023 16 3 10.1186/s13045-022-01397-y 36650546 PMC9847035
62. Sletten E.M. Bertozzi C.R. Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of Functionality Angew. Chem. Int. Ed. 2009 48 6974 6998 10.1002/anie.200900942 19714693 PMC2864149
63. Bargh J.D. Isidro-Llobet A. Parker J.S. Spring D.R. Cleavable linkers in antibody–drug conjugates Chem. Soc. Rev. 2019 48 4361 4374 10.1039/C8CS00676H 31294429
64. Huang B.C.B. Kim Y.C. Bañas S. Barfield R.M. Drake P.M. Rupniewski I. Haskins W.E. Rabuka D. Antibody-drug conjugate library prepared by scanning insertion of the aldehyde tag into IgG1 constant regions mAbs 2018 10 1182 1189 10.1080/19420862.2018.1512327 30252630 PMC6284588
65. Marei H.E. Cenciarelli C. Hasan A. Potential of antibody–drug conjugates (ADCs) for cancer therapy Cancer Cell Int. 2022 22 255 10.1186/s12935-022-02679-8 35964048 PMC9375290
66. Tsuchikama K. An Z. Antibody-drug conjugates: Recent advances in conjugation and linker chemistries Protein Cell 2016 9 33 46 10.1007/s13238-016-0323-0 27743348 PMC5777969
67. Csikós Z. Fazekas E. Rózsa D. Borbély J. Kerekes K. Crosslinked poly-γ-glutamic acid based nanosystem for drug delivery J. Drug Deliv. Sci. Technol. 2018 48 478 489 10.1016/j.jddst.2018.10.026
68. Csikós Z. Kerekes K. Fazekas E. Kun S. Borbély J. Biopolymer based nanosystem for doxorubicin targeted delivery Am. J. Cancer Res. 2017 7 715 726 28401023 PMC5385654
69. Marques A.C. Costa P.C. Velho S. Amaral M.H. Lipid Nanoparticles Functionalized with Antibodies for Anticancer Drug Therapy Pharmaceutics 2023 15 216 10.3390/pharmaceutics15010216 36678845 PMC9864942
70. Aptamer Group and PinotBio Extend Collaboration for the Development of Optimer-Drug Conjugates Available online: https://aptamergroup.com/aptamer-group-and-pinotbio-extend-collaboration-for-the-development-of-optimer-drug-conjugates/ (accessed on 23 May 2022)
71. Aptamer Group and PinotBio Extend Collaboration Available online: https://markets.ft.com/data/announce/detail?dockey=1323-15463214-6M6DQKFL242JNP55NP7RKRB7S6 (accessed on 23 May 2022)
72. ADC Therapeutics Announces Results from Pivotal Phase 2 Clinical Trial of Camidanlumab Tesirine (Cami) in Relapsed or Refractory Hodgkin Lymphoma Available online: https://ir.adctherapeutics.com/press-releases/press-release-details/2022/ADC-Therapeutics-Announces-Results-from-Pivotal-Phase-2-Clinical-Trial-of-Camidanlumab-Tesirine-Cami-in-Relapsed-or-Refractory-Hodgkin-Lymphoma/default.aspx (accessed on 10 June 2022)
73. Spirea Raises £2.4M in Funding Available online: https://www.finsmes.com/2022/06/spirea-raises-2-4m-in-funding.html (accessed on 14 June 2022)
74. FDA Grants Regular Approval to Fam-Trastuzumab Deruxtecan-Nxki for Breast Cancer Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-fam-trastuzumab-deruxtecan-nxki-breast-cancer (accessed on 5 November 2022)
75. Burden N. Aschberger K. Chaudhry Q. Clift M.J.D. Fowler P. Johnston H. Landsiedel R. Rowland J. Stone V. Doak S.H. Aligning nanotoxicology with the 3Rs: What is needed to realise the short, medium and long-term opportunities? Regul. Toxicol. Pharmacol. 2017 91 257 266 10.1016/j.yrtph.2017.10.021 29069581
76. Hogle L.F. Concepts of Risk in Nanomedicine Research J. Law Med. Ethics 2012 40 809 822 10.1111/j.1748-720X.2012.00709.x 23289683
77. Accomasso L. Cristallini C. Giachino C. Risk assessment and risk minimization in nanomedicine: A need for predictive, alternative, and 3Rs strategies Front. Pharmacol. 2018 9 228 10.3389/fphar.2018.00228 29662451 PMC5890110
78. Schuhmacher A. Gassmann O. Hinder M. Changing R & D models in research-based pharmaceutical companies J. Transl. Med. 2016 14 105 10.1186/s12967-016-0838-4 27118048 PMC4847363
79. Domonkos D. Hronszki I. Risk Assessment of Innovations in The Biopharmaceutical Industry/Book 2 IntechOpen Rijeka, Croatia 2012 85 104
80. Baah S. Laws M. Rahman K.M. Antibody–Drug Conjugates—A Tutorial Review Molecules 2021 26 2943 10.3390/molecules26102943 34063364 PMC8156828
81. Fu Z. Li S. Han S. Shi C. Zhang Y. Antibody drug conjugate: The “biological missile” for targeted cancer therapy Signal Transduct. Target. Ther. 2022 7 93 10.1038/s41392-022-00947-7 35318309 PMC8941077
82. Mathur R. Weiner G.J. Picking the Optimal Target for Antibody-Drug Conjugates Am. Soc. Clin. Oncol. Educ. Book 2013 33 e103 e107 10.14694/EdBook_AM.2013.33.e103 23714470
83. Haubenreisser S. EMA perspective on the development of Nanomedicines Proceedings of the PQRI Nanotechnology Workshop Washington, DC, USA 14–15 January 2014
84. Pepić I. Hafner A. Lovrić J. Lakos G.P. Nanotherapeutics in the EU: An overview on current state and future directions Int. J. Nanomed. 2014 9 1005 1023 10.2147/IJN.S55359 PMC3933707 24600222
85. Hardison S. Oncology Dealmaking in 2020 Biopharm. Deal. 2021 B5 Available online: https://www.nature.com/articles/d43747-021-00024-y (accessed on 27 December 2022) 2730-6283
86. Sambandan P. Raja H.B. Open Innovation in Pharmaceutical Industry, a Case Study of Eli Lilly: How Do Big Pharmas Implement OI?—A Critical Analysis of the Current OI Practices through a Case Study Master’s Thesis Department of Industrial Economics and Management (INDEK), KTH School of Industrial Engineering and Management (ITM) Stockholm, Sweden 2015
87. Manning S. The rise of project network organizations: Building core teams and flexible partner pools for interorganizational projects Res. Policy 2017 46 1399 1415 10.1016/j.respol.2017.06.005
88. Tong J.T.W. Harris P.W.R. Brimble M.A. Kavianinia I. An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy Molecules 2021 26 5847 10.3390/molecules26195847 34641391 PMC8510272
89. Yu S. Lim A. Tremblay M.S. Next Horizons: ADCs Beyond Oncology Innovations for Next-Generation Antibody-Drug Conjugates Damelin M. Humana Press Cham, Switzerland 2018 321 347 10.1007/978-3-319-78154-9_14