Business Risk Mitigation in the Development Process of New Monoclonal Antibody Drug Conjugates for Cancer Treatment
Abstract
:1. Introduction
2. The Market of ADCs
3. Nanotechnology in Medical Biotechnology
3.1. Nanoparticle-Based Drug Delivery
3.2. Gene Therapy
3.3. Photodynamic Therapy
3.4. Immunotherapy
3.5. Tissue Engineering
3.6. Diagnostic Imaging
4. R&D of ADC Technologies
- 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].
5. Challenges and Business Risks in R&D of ADCs
5.1. Risks for R&D, Limits, and Failures
- 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.
- 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.
- 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.
- 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.
5.2. Case Studies
5.3. New Forms for R&D
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ADC | Antibody–Drug Conjugate |
mAb | Monoclonal Antibody |
HER | Human Epidermal Growth Factor |
TZM | Trastuzumab |
CAGR | Compound Annual Growth Rate |
ADCC | Antibody-Dependent Cell-Mediated Cytotoxicity |
CDC | Complement-Dependent Cytotoxicity |
MRI | Magnetic Resonance Imaging |
CT | Computer Tomography |
ACNP | Antibody-Conjugated Nanoparticle |
NPDC | Nanoparticle–Drug Conjugate |
PDUFA | Prescription Drug User Fee Act |
ROI | Return of Investment |
NME | New Molecular Entity |
M&A | Mergers and Acquisitions |
PBF | Project-Based Firm |
PNO | Project Network Organization |
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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 |
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Kiss, B.; Borbély, J. Business Risk Mitigation in the Development Process of New Monoclonal Antibody Drug Conjugates for Cancer Treatment. Pharmaceutics 2023, 15, 1761. https://doi.org/10.3390/pharmaceutics15061761
Kiss B, Borbély J. Business Risk Mitigation in the Development Process of New Monoclonal Antibody Drug Conjugates for Cancer Treatment. Pharmaceutics. 2023; 15(6):1761. https://doi.org/10.3390/pharmaceutics15061761
Chicago/Turabian StyleKiss, Balázs, and János Borbély. 2023. "Business Risk Mitigation in the Development Process of New Monoclonal Antibody Drug Conjugates for Cancer Treatment" Pharmaceutics 15, no. 6: 1761. https://doi.org/10.3390/pharmaceutics15061761
APA StyleKiss, B., & Borbély, J. (2023). Business Risk Mitigation in the Development Process of New Monoclonal Antibody Drug Conjugates for Cancer Treatment. Pharmaceutics, 15(6), 1761. https://doi.org/10.3390/pharmaceutics15061761