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Bispecific Antibody...
Bispecific Antibody Molecule Inhibits Tumor Cell Proliferation More Efficiently Than the Two-Molecule Combination
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- Volk, Anna-Luisa (author)
- KTH,Proteinteknologi,Albanova VinnExcellence Center for Protein Technology, ProNova,KTH Royal Inst Technol, AlbaNova Univ Ctr, Sch Engn Sci Biotechnol Chem & Hlth, S-10691 Stockholm, Sweden.
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- Mebrahtu, Aman (author)
- KTH,Proteinteknologi,Albanova VinnExcellence Center for Protein Technology, ProNova,KTH Royal Inst Technol, AlbaNova Univ Ctr, Sch Engn Sci Biotechnol Chem & Hlth, S-10691 Stockholm, Sweden.
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- Ko, B. -K (author)
- AbClon Inc, Seoul 152779, South Korea.
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- Lundqvist, Magnus (author)
- KTH,Proteinteknologi,Albanova VinnExcellence Center for Protein Technology, ProNova,KTH Royal Inst Technol, AlbaNova Univ Ctr, Sch Engn Sci Biotechnol Chem & Hlth, S-10691 Stockholm, Sweden.
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- Karlander, Maximilian (author)
- KTH,Albanova VinnExcellence Center for Protein Technology, ProNova,Proteinteknologi,KTH Royal Inst Technol, AlbaNova Univ Ctr, Sch Engn Sci Biotechnol Chem & Hlth, S-10691 Stockholm, Sweden.
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- Lee, H. -J (author)
- AbClon Inc, Seoul 152779, South Korea.
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- Frejd, Fredrik Y. (author)
- Uppsala universitet,Medicinsk strålningsvetenskap,Affibody AB, S-17169 Solna, Sweden.
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- Kim, K. -T (author)
- AbClon Inc, Seoul 152779, South Korea.
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- Lee, J. -S (author)
- AbClon Inc, Seoul 152779, South Korea.
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- Rockberg, Johan (author)
- KTH,Proteinteknologi,Albanova VinnExcellence Center for Protein Technology, ProNova,KTH Royal Inst Technol, AlbaNova Univ Ctr, Sch Engn Sci Biotechnol Chem & Hlth, S-10691 Stockholm, Sweden.
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(creator_code:org_t)
- 2021-03-15
- 2021
- English.
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In: Drugs in R&D. - : Adis. - 1174-5886 .- 1179-6901. ; 21:2, s. 157-168
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Abstract
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- Background: Monoclonal antibodies (mAbs) have proved to be a valuable tool for the treatment of different cancer types. However, clinical use of an increasing number of mAbs, have also highlighted limitations with monotherapy for cancers, in particular for such with more complex mechanisms, requiring action on additional molecules or pathways, or for cancers quickly acquiring resistance following monotherapy. An example for the latter is the mAb trastuzumab, FDA approved for treatment of metastatic gastric carcinoma. To circumvent this, researchers have reported synergistic, anti-proliferative effects by combination targeting of HER2 and EGFR by trastuzumab and the EGFR-targeting mAb Cetuximab overcoming trastuzumab resistance. Methods: Maintaining the proven functionality of trastuzumab, we have designed bi-specific antibody molecules, called AffiMabs, by fusing an EGFR-targeting Affibody molecule to trastuzumab’s heavy or light chains. Having confirmed binding to EGFR and Her2 and cytotoxicity of our AffiMabs, we analyzed apoptosis rate, receptor surface levels, phosphorylation levels of receptors and associated signaling pathways as well as differentially expressed genes on transcriptome level with the aim to elucidate the mode of action of our AffiMabs. Results: The AffiMabs are able to simultaneously bind HER2 and EGFR and show increased cytotoxic effect compared to the original trastuzumab therapeutic molecule and, more importantly, even to the combination of trastuzumab and EGFR-targeting Affibody molecule. Analyzing the mode of action, we could show that bi-specific AffiMabs lead to reduced surface receptor levels and a downregulation of cell cycle associated genes on transcriptome level. Conclusion: Our study shows that transcriptome analysis can be used to validate the choice of receptor targets and guide the design of novel multi-specific molecules. The inherent modularity of the AffiMab format renders it readily applicable to other receptor targets.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- adalimumab
- bispecific antibody
- cetuximab
- epidermal growth factor receptor
- epidermal growth factor receptor 2
- epidermal growth factor receptor 3
- messenger RNA
- phosphatidylinositol 3 kinase
- trastuzumab
- monoclonal antibody
- A-431 cell line
- antiproliferative activity
- apoptosis rate
- Article
- cancer inhibition
- cancer resistance
- carboxy terminal sequence
- cell proliferation
- cell proliferation assay
- comparative study
- controlled study
- cytotoxicity
- female
- flow cytometry
- human
- human cell
- NCI-N87 cell line
- protein binding
- protein phosphorylation
- signal transduction
- SK-OV-3 cell line
- surface plasmon resonance
- surface property
- tumor cell
- neoplasm
- Antibodies
- Monoclonal
- Antibodies
- Monoclonal
- Humanized
- Humans
- Neoplasms
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Volk, Anna-Luisa
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Mebrahtu, Aman
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Ko, B. -K
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Lundqvist, Magnu ...
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Karlander, Maxim ...
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Lee, H. -J
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show more...
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Frejd, Fredrik Y ...
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Kim, K. -T
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Lee, J. -S
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Rockberg, Johan
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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Drugs in R&D
- By the university
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Royal Institute of Technology
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Uppsala University