Antibody–Drug Conjugates: A Novel Paradigm for Cancer Therapy
Whitepaper
Last Updated: October 11, 2023
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Published: September 13, 2023
Credit: iStock
Chemotherapy is one of the most widely used treatment approaches for cancer. However, it can often cause serious side effects, posing challenges for drug developers.
Antibody–drug conjugates (ADCs) combine the effective killing power of small molecule cytotoxins and the highly specific targeting ability of monoclonal antibodies, and so can precisely deliver cytotoxins to tumor cells, while minimally affecting normal cells.
This whitepaper highlights the key molecular components of ADCs and the challenges and opportunities for their future development.
Download this whitepaper to learn more about:
- Currently approved ADCs and their indications
- The mechanism of action of ADC drugs
- Overcoming cytotoxic payload challenges in drug development
Chemotherapy is one of the most widely used cancer therapies; however,
chemotherapy often causes serious side effects. Antibody-drug conjugates
(ADCs) are promisingly emerging cancer therapies that combine the
effective killing power of small molecule cytotoxins and the highly specific
targeting ability of monoclonal antibodies (mAbs). Thus, ADCs precisely
deliver cytotoxins to tumor cells, while minimally affecting normal cells.
ADCs have become a hot spot for anticancer drug development1,2.
The first-generation ADC, gemtuzumab ozogamicin, was approved by the
U.S. Food and Drug Administration (FDA) in 2000. Since then, multiple ADCs
have been approved worldwide, and more than 100 ADC candidates have
entered the clinical phase. These new anticancer drugs are leading the way
to a new cancer therapy phase.
Table. 1 Currently approved ADCs on the market.
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Targets Drugs Approval Indications
CD33 Gemtuzumab ozogamicin 2000-FDA;2017-FDA Acute myeloid leukemia
CD30 Brentuximab vedotin 2011-FDA Hodgkin lymphoma
HER2 Trastuzumab emtansine 2013-FDA Breast cancer
CD22 Inotuzumab ozogamicin 2017-FDA Acute myeloid leukemia
CD22 Moxetumomab pasudotox 2018-FDA Hairy cell leukemia
CD79 Polatuzumab vedotin 2019-FDA Diffuse large B-cell lymphoma
Nectin4 Enfortumab vedotin 2019-FDA Advanced urothelial cancer
HER2 Trastuzumab deruxtecan 2019-FDA Breast cancer
TROP2 Sacituzumab govitecan 2020-FDA Triple-negative breast cancer
EGFR Cetuximab Saratolacan 2020-MHLW Head and neck cancer
BCMA Belantamab mafodotin 2020-FDA: Withdrawal in 2022 Multiple myeloma
CD19 Loncastuximab tesirine 2021-FDA Large B-cell lymphoma
Tissue factor Tisotumab vedotin-tftv 2021-FDA Cervical cancer
HER2 Disitamab vedotin 2021-NMPA Gastric or gastroesophageal cancer
FRα Mirvetuximab soravtansine 2022-FDA Ovarian Cancer
Antibody-drug Conjugates:
A Novel Paradigm for
Cancer Therapy
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+49(0)6196 9678656
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Target antigens should be non-secretory, expressed mainly on the tumor cell surface, and expressed at low levels in normal tissues. In
addition, target antigens should be internalized after binding to the corresponding antibodies to facilitate the entry of ADC-antigen
complexes into tumor cells to release cytotoxic payloads via an appropriate intracellular translocation route4.
At present, the target antigens for approved ADC drugs are specific proteins overexpressed in tumor cells, including HER2, Trop2, Nectin4, and
EGFR in solid tumors, and CD19, CD22, CD33, CD30, BCMA, and CD79 in hematologic malignancies. Emerging targets, such as EpCAM, CD70,
CD25, CD166, and others, are under development and showing promising results5. Sino Biological is at the forefront of the ADC therapy field,
providing quality products for ADC target antigens.
(1) Well-established targets: EGFR, HER2, and CD22
Target Antigens
Figure 1. The general mechanism of action for antibody-drug conjugates (ADCs).
Immobilized Human EGF
(Cat#: 10605-H01H) can bind Human EGFR
An ADC consists of a target-specific mAb, a cytotoxic payload, and a chemically synthesized linker that covalently links the toxin and the
antibody. The mAb binds to specific antigens on the surface of tumor cells, and ADCs are internalized into tumor cells during the formation
of antibody-antigen complexes. ADCs are typically transported from the endosome to the lysosome, where the linker is cleaved and the
small molecule cytotoxins are released, leading to tumor cell death3. Overall, ADC development requires consideration of the target antigens,
antibodies, cytotoxic payload, and linker (Figure 1).
Key Components of ADCs
1. ADCs 2. Binding to
antigen target
3. Receptor-mediated
endocytosis
4. ADC in endosome
5. Drug released
from ADC in
lysosome
6. Free drug
in cytosol
7. Cell death
Linker Cytotoxin
Antibody
0
0.5
1.5
2.0
2.5
1.0
EC50=60-480 ng/mL
1 10 100 1000 10000
Human EGFR Conc. (ng/mL)
Abs.(OD450nm-Blank)
Human EGFR Protein
Cat#: 10001-H27H-B
Immobilized Anti-Erbb2 Antibody can bind
Human HER2 / ErbB2 Protein
0.0
-0.5
0.5
2.5
2.0
3.0
3.5
4.0
1.5
1.0
EC50=1.25-3.75 ng/mL
0.01 0.1 1 10 100
Anti-HER2 Antibody Conc. (ng/mL)
Abs.(OD450nm-Blank)
Human HER2/ERBB2 Protein
Cat#: 10004-H27H2-B
Immobilized human CD22 can bind
anti-human CD22 Mab
0.5
0.0
1.0
2.0
3.0
2.5
3.5
1.5
EC50=0.2-50 ng/mL
10 100
Anti-CD22Antibody Conc. (ng/mL)
Abs.(OD450nm-Blank)
Human CD22 Protein
Cat#: 11958-H08H
(2) Emerging targets: CD70, CD166, and CD25
Immunoglobulins (IgGs) and their derivatives are commonly used in clinical studies. IgG1, IgG2, and IgG4 are mainly used for ADCs because
of their specificity, affinity for the target antigen, and long circulating half-life. In addition, the antibodies should possess effective
internalization ability and low immunogenicity6.
In early ADC drug development, predominantly mouse antibodies were used. However, these antibodies elicited a significant immune
response, resulting in reduced therapeutic efficacy. With the advent of recombinant technology, mouse antibodies have been replaced with
chimeric and humanized antibodies. Currently, ADCs increasingly use fully humanized antibodies with significantly lower immunogenicity7
.
Sino Biological provides high-quality mAb humanization services using complementarity-determining region (CDR) grafting technology
and computer-aided molecular modeling. In addition, Sino Biological possesses the high-throughput and scale-up capabilities to produce
highly efficient antibodies in HEK293 and CHO cells in as fast as 2 weeks, with over 1000 Abs expression per batch.
Antibodies
Cytotoxins should have high toxicity, low immunogenicity, and high stability. In addition, the cytotoxin should have a modifiable functional
group or a site where a functional group can be introduced to link the mAb. The most commonly used cytotoxins for ADC drugs on the market
or in clinical trials are microtubule protein inhibitors or DNA-damaging agents8. Additionally, the drug-antibody ratio (DAR), i.e. the number
of drug molecules attached to the antibody by the linker, is a key factor in ADC development. A low DAR may reduce ADC efficacy, while a
high DAR may cause instability, leading to off-target toxicity8,9.
Cytotoxic Payload
Figure 2. High-quality target antigen products.
Figure 3. The process of antibody humanization and complementarity-determining region (CDR) grafting technology.
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Sino Biological US Inc. (U.S.A.)
+1-215-583-7898
order_us@sinobiologicalus.com
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+49(0)6196 9678656
order_eu@sinobiologicaleu.com
Sino Biological, Inc. (Global)
+86-400-890-9989
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株式会社日本シノバイオロジカル (Japan)
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Immobilized Human CD27
(Cat#: 10039-H08B1) can bind Human CD70
Human CD70 Protein
Cat#: 10780-H01H
Immobilized human CD166 can bind
mouse CD6
Human CD166/ALCAM Protein
Cat#: 10045-H08H
Ability to inhibit IL2-induced proliferation of
M07e cells
Human CD25/IL2R alpha Protein
Cat#: 10165-H08H
0
2
3
4
1
EC50=15-60 ng/mL
1 10 100 1000 10000
Human CD70 Conc. (ng/mL)
Abs.(OD450nm-Blank)
0
1
3
4
5
2
EC50=0.1-0.22 µg/mL
0.1 1 10 100 1000 10000
Mouse CD6 Conc. (ng/mL)
Abs.(OD450nm-Blank)
-20
0
40
60
80
100
20
ED50=0.2-1.2 µg/mL
1E-3 0.01 0.1 1 10
Human IL2Rα Conc. (µg/mL)
Inhibition,%
Mouse Antibody
Humanized Antibody
Mouse Antibody
Human Framework Region
Humanized Antibody
CDR Identification & 3D Structural Modeling
CDR Grafting
Back Mutations
FR1 CDR1 FR2 CDR2 FR3 CDR3 FR4
FR1 CDR1 FR2 CDR2 FR3 CDR3 FR4
FR1 CDR1 FR2 CDR2 FR3 CDR3 FR4
The linker ensures that the cytotoxic payload remains firmly attached to the antibody in the plasma during circulation, avoiding premature
release that would damage normal tissues or cells and ensuring the effective release within the target tumor cells. Linkers can be classified
as cleavable and non-cleavable. Cleavable linkers take advantage of the environmental differences between the circulation and tumor
cells to accurately release free cytotoxins. Non-cleavable linkers depend on lysosomal degradation of the entire antibody-linker structure,
which results in the retention of charged amino acids in the payload10,11.
Linker
Figure 4. Sino Biological bispecific antibody
production service highlights.
Many challenges remain in ADC development. The biggest challenge is the toxic effects
of ADCs, including neutropenia, thrombocytopenia, leukopenia, anemia, and
gastrointestinal effects4. Another challenge is tumor resistance to ADCs, as evidenced by
reduced antigen expression levels, altered intracellular transport pathways, and payload
resistance. In addition, payload release is a challenge. The ADCs are much larger than
traditional cytotoxic drugs, and the efficiency of cytotoxin penetration into tumors is
limited.
To overcome these challenges, future ADC development should focus on the following:
(1) improvements in ADC design to reduce toxicity, including payload platforms, linkers,
and coupling strategies; (2) use of two cytotoxic agents as payloads to reduce ADC
resistance; and (3) enhancing ADC internalization and lysosomal delivery through
bispecific antibodies to improve antitumor specificity. Sino Biological utilizes an
optimized mammalian cell expression platform to provide fast and efficient bispecific
antibody expression services for clients worldwide12.
Challenges and Perspectives
References
1. Fu Z, Li S, Han S, et al. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduction and Targeted
Therapy. 2022;7(1):93. doi: 10.1038/s41392-022-00947-7
2. Schwach J, Abdellatif M, Stengl A. More than Toxins—Current Prospects in Designing the Next Generation of Antibody Drug Conjugates.
Frontiers in Bioscience-Landmark. 2022;27(8):240. doi: 10.31083/j.fbl2708240
3. Tang H, Liu Y, Yu Z, et al. The analysis of key factors related to ADCs structural design. Frontiers in Pharmacology. 2019;10:373.
doi: 10.3389/fphar.2019.00373
4. Zhao P, Zhang Y, Li W, et al. Recent advances of antibody drug conjugates for clinical applications. Acta Pharmaceutica Sinica B.
2020;10(9):1589-1600. doi: 10.1016/j.apsb.2020.04.012
5. Hafeez U, Parakh S, Gan HK, et al. Antibody–drug conjugates for cancer therapy. Molecules. 2020;25(20):4764.
doi: 10.3390/molecules25204764
6. Zhang X, Huang AC, Chen F, et al. Novel development strategies and challenges for anti-Her2 antibody-drug conjugates. Antibody
Therapeutics. 2022;5(1):18-29. doi: 10.1093/abt/tbac001
7. Khongorzul P, Ling CJ, Khan FU, et al. Antibody–Drug Conjugates: A Comprehensive ReviewAntibody–Drug Conjugates in Cancer
Immunotherapy. Molecular Cancer Research. 2020;18(1):3-19. doi: 10.1158/1541-7786.MCR-19-0582
8. Ziad A, Abdurahman A, Misako N. A comprehensive review on antibody-drug conjugates (ADCs) in the treatment landscape of non-small
cell lung cancer (NSCLC). Cancer Treatment Reviews. 2022;102393. doi: 10.1016/j.ctrv.2022.102393
9. Sheyi R, de la Torre BG, Albericio F. Linkers: An Assurance for Controlled Delivery of antibody-drug conjugate. Pharmaceutics. 2022;14(2):396.
doi: 10.3390/pharmaceutics14020396
10. Tong JTW, Harris PWR, Brimble MA, et al. An insight into FDA approved antibody-drug conjugates for cancer therapy. Molecules.
2021;26(19):5847. doi: 10.3390/molecules26195847
11. Ungaro A, Tucci M, Audisio A, et al. Antibody-drug conjugates in urothelial carcinoma: a new therapeutic opportunity moves from bench to
bedside. Cells. 2022;11(5):803. doi: 10.3390/cells11050803
12. Yu J, Fang T, Yun C, et al. Antibody-drug conjugates targeting the human epidermal growth factor receptor family in cancers. Frontiers in
Molecular Biosciences. 2022;9:184. doi: 10.3389/fmolb.2022.847835
www.sinobiological.com
Sino Biological US Inc. (U.S.A.)
+1-215-583-7898
order_us@sinobiologicalus.com
Sino Biological Europe GmbH (Europe)
+49(0)6196 9678656
order_eu@sinobiologicaleu.com
Sino Biological, Inc. (Global)
+86-400-890-9989
order@sinobiological.com
株式会社日本シノバイオロジカル (Japan)
044-400-1330
order@sinobiological.co.jp
ADC therapy has benefited many cancer patients. In the future, the therapeutic efficacy of ADC will be improved by reducing ADC toxicity
and drug resistance. Sino Biological will continue to be at the forefront of the ADC therapy field, providing researchers and pharmaceutical
companies with high-quality products and one-stop services.
Optimized HEK293/
CHO Platforms
Completed numerous bsAb production
projects with >90% of overall success rates
1. Better post-translational modifications
2. Easier to scale up production
>90%
Success Rate
Expression Systems
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