Differential tumor-targeting abilities of three single-domain antibody formats

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• 作者：Andrea Bell ; Zheng J. Wang ; Mehdi Arbabi-Ghahroudi ; Tingtung A. Chang ; Yves Durocher ; Ulrike Trojahn ; Jason Baardsnes ; Maria L. Jaramillo ; Shenghua Li ; Toya N. Baral ; Maureen O’ ; Connor-McCourt
• 关键词：Epidermal growth factor receptor ; (Chimeric) heavy chain antibody ; Single-domain antibody
• 刊名：Cancer Letters
• 出版年：2010
• 出版时间：1 March 2010
• 年：2010
• 卷：289
• 期：1
• 页码：81-90
• 全文大小：728 K

文摘

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.