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Updated: Aug 9, 2026
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A GPC3-targeting Bispecific Antibody, GPC3-S-Fab, with Potent Cytotoxicity
Published on: July 12, 2018
A CDR-grafted (humanized) domain-deleted antitumor antibody
D C Slavin-Chiorini1, S V Kashmiri, H S Lee
1Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health Bethesda, Maryland 20892, USA.
Cancer Biotherapy & Radiopharmaceuticals
|June 14, 2000
Summary
This study developed a novel recombinant antibody (HuCC49 delta CH2) that shows faster clearance and reduced immunogenicity for improved cancer radioimmunodiagnosis and radioimmunotherapy targeting TAG-72. This engineered antibody offers enhanced tumor targeting with lower toxicity.
Area of Science:
- Biotechnology
- Immunology
- Oncology
Background:
- Murine monoclonal antibodies (MAbs) show promise for cancer targeting but face challenges like host anti-immunoglobulin responses and slow plasma clearance.
- These limitations hinder diagnostic applications (delayed tumor detection) and therapeutic efficacy (bone marrow toxicity).
Purpose of the Study:
- To develop a recombinant immunoglobulin (Ig) with reduced immunogenicity and faster plasma clearance for improved radioimmunotherapy and radioimmunodiagnosis.
- To engineer a humanized (Hu) MAb with a CH2 domain deletion (delta CH2) targeting the pancarcinoma antigen TAG-72.
Main Methods:
- Engineered a complementarity determining region (CDR)-grafted humanized MAb (CC49) with a CH2 domain deletion (HuCC49 delta CH2).
- Characterized antigen binding affinity and performed plasma clearance and biodistribution studies in athymic and SCID mice bearing human colon carcinoma xenografts.
- Compared HuCC49 delta CH2 with intact HuCC49 and murine CC49.
Main Results:
- HuCC49 delta CH2 demonstrated complete inhibition of TAG-72 binding, with a relative affinity constant (Ka) of 5.1 x 10(-9).
- Significantly faster plasma clearance of 131I-HuCC49 delta CH2 compared to 125I-HuCC49 in both athymic and SCID mice.
- Efficient tumor localization and substantially lower uptake in normal tissues, resulting in higher radiolocalization indices for HuCC49 delta CH2.
Conclusions:
- The novel HuCC49 delta CH2 recombinant Ig molecule combines rapid blood clearance and reduced potential for eliciting human anti-murine antibody (HAMA) responses.
- Demonstrated potential utility for both intraperitoneal (i.p.) and intravenous (i.v.) radioimmunodiagnosis and radioimmunotherapy in patients with TAG-72 positive tumors.
