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Tytuł pozycji:

Improvement of Biophysical Properties and Affinity of a Human Anti-L1CAM Therapeutic Antibody through Antibody Engineering Based on Computational Methods.

Tytuł:
Improvement of Biophysical Properties and Affinity of a Human Anti-L1CAM Therapeutic Antibody through Antibody Engineering Based on Computational Methods.
Autorzy:
Chae H; Department of Systems Immunology, Kangwon National University, Chuncheon 24341, Korea.; APIT BIO Inc., B910, Munjeongdong Tera Tower, 167 Songpa-daero, Songpa-gu, Seoul 05855, Korea.
Cho S; Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon 24341, Korea.
Jeong M; Department of Systems Immunology, Kangwon National University, Chuncheon 24341, Korea.
Kwon K; Department of Systems Immunology, Kangwon National University, Chuncheon 24341, Korea.
Choi D; Division of Drug Process Development, New Drug Development Center, Osong Medical Innovation Foundation, Chungcheongbuk-do, Cheongju-si 28160, Korea.
Lee J; APIT BIO Inc., B910, Munjeongdong Tera Tower, 167 Songpa-daero, Songpa-gu, Seoul 05855, Korea.
Nam W; APIT BIO Inc., B910, Munjeongdong Tera Tower, 167 Songpa-daero, Songpa-gu, Seoul 05855, Korea.
Hong J; Department of Systems Immunology, Kangwon National University, Chuncheon 24341, Korea.
Lee J; Department of Systems Immunology, Kangwon National University, Chuncheon 24341, Korea.
Yoon S; APIT BIO Inc., B910, Munjeongdong Tera Tower, 167 Songpa-daero, Songpa-gu, Seoul 05855, Korea.
Hong H; Department of Systems Immunology, Kangwon National University, Chuncheon 24341, Korea.; Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon 24341, Korea.
Źródło:
International journal of molecular sciences [Int J Mol Sci] 2021 Jun 22; Vol. 22 (13). Date of Electronic Publication: 2021 Jun 22.
Typ publikacji:
Journal Article
Język:
English
Imprint Name(s):
Original Publication: Basel, Switzerland : MDPI, [2000-
MeSH Terms:
Models, Molecular*
Protein Engineering*/methods
Antibodies, Monoclonal/*chemistry
Neural Cell Adhesion Molecule L1/*chemistry
Animals ; Antibodies, Monoclonal/genetics ; Antibodies, Monoclonal/pharmacology ; Antibody Affinity ; CHO Cells ; Chemical Phenomena ; Cricetulus ; Drug Design ; Drug Evaluation, Preclinical ; Humans ; Neural Cell Adhesion Molecule L1/antagonists & inhibitors ; Protein Stability ; Thermodynamics
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Grant Information:
KDDF-201212-12 Korea Drug Development Fund; NRF-2018R1D1A1A09084274 Basic Science Research Program grant; 10449069 BIG3 Innovative startup package support Program; S3029721 Technology development Program
Contributed Indexing:
Keywords: anti-cancer antibody; antibody engineering; biophysical properties; computational methods; research cell bank; therapeutic antibody
Substance Nomenclature:
0 (Antibodies, Monoclonal)
0 (L1CAM protein, human)
0 (Neural Cell Adhesion Molecule L1)
Entry Date(s):
Date Created: 20210702 Date Completed: 20210723 Latest Revision: 20210723
Update Code:
20240105
PubMed Central ID:
PMC8268072
DOI:
10.3390/ijms22136696
PMID:
34206616
Czasopismo naukowe
The biophysical properties of therapeutic antibodies influence their manufacturability, efficacy, and safety. To develop an anti-cancer antibody, we previously generated a human monoclonal antibody (Ab417) that specifically binds to L1 cell adhesion molecule with a high affinity, and we validated its anti-tumor activity and mechanism of action in human cholangiocarcinoma xenograft models. In the present study, we aimed to improve the biophysical properties of Ab417. We designed 20 variants of Ab417 with reduced aggregation propensity, less potential post-translational modification (PTM) motifs, and the lowest predicted immunogenicity using computational methods. Next, we constructed these variants to analyze their expression levels and antigen-binding activities. One variant (Ab612)-which contains six substitutions for reduced surface hydrophobicity, removal of PTM, and change to the germline residue-exhibited an increased expression level and antigen-binding activity compared to Ab417. In further studies, compared to Ab417, Ab612 showed improved biophysical properties, including reduced aggregation propensity, increased stability, higher purification yield, lower pI, higher affinity, and greater in vivo anti-tumor efficacy. Additionally, we generated a highly productive and stable research cell bank (RCB) and scaled up the production process to 50 L, yielding 6.6 g/L of Ab612. The RCB will be used for preclinical development of Ab612.
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