Differential tumor-targeting abilities of three single-domain antibody formats
| Autor: | Shenghua Li, Maria L. Jaramillo, Yves Durocher, Jason Baardsnes, Jianbing Zhang, Toya Nath Baral, Roger MacKenzie, Maureen D. O'Connor-McCourt, Mehdi Arbabi-Ghahroudi, Zheng J. Wang, Ulrike Trojahn, Tingtung A. Chang, Andrea Bell |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Cancer Research Tumor targeting Phage display Molecular Sequence Data Protein domain Protein Engineering Mice Drug Delivery Systems Cell Line Tumor Animals Humans Amino Acid Sequence Epidermal growth factor receptor Immunoglobulin Fragments Mice Inbred BALB C Heavy chain biology Molecular biology ErbB Receptors Pancreatic Neoplasms Single-domain antibody Oncology biology.protein Female Antibody Camelids New World Sequence Alignment Preclinical imaging |
| Zdroj: | Cancer Letters. 289:81-90 |
| ISSN: | 0304-3835 |
| DOI: | 10.1016/j.canlet.2009.08.003 |
| Popis: | The large molecular size of antibody drugs is considered one major factor preventing them from becoming more efficient therapeutics. Variable regions of heavy chain antibodies (HCAbs), or single-domain antibodies (sdAbs), are ideal building blocks for smaller antibodies due to their molecular size and enhanced stability. In the search for better antibody formats for in vivo imaging and/or therapy of cancer, three types of sdAb-based molecules directed against epidermal growth factor receptor (EGFR) were constructed, characterized and tested. Eleven sdAbs were isolated from a phage display library constructed from the sdAb repertoire of a llama immunized with a variant of EGFR. A pentameric sdAb, or pentabody, V2C-EG2 was constructed by fusing one of the sdAbs, EG2, to a pentamerization protein domain. A chimeric HCAb (cHCAb), EG2-hFc, was constructed by fusing EG2 to the fragment crystallizable (Fc) of human IgG1. Whereas EG2 and V2C-EG2 localized mainly in the kidneys after i.v. injection, EG2-hFc exhibited excellent tumor accumulation, and this was largely attributed to its long serum half life, which is comparable to that of IgGs. The moderate size (∼80 kDa) and intact human Fc make HCAbs a unique antibody format which may outperform whole IgGs as imaging and therapeutic reagents. |
| Databáze: | OpenAIRE |
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