Synthesis and evaluation of the aldolase antibody-derived chemical-antibodies targeting α5β1 integrin.

Abstract

Integrin α5β1 is an important therapeutic target that can be inhibited using an aldolase antibody (Ab)-derived chemical-Ab (chem-Ab) for the treatment of multiple human diseases, including cancers. A fairly optimized anti-integrin α5β1 chem-Ab 38C2-4e was obtained using an in situ convergent chemical programming (CP) approach, which minimized the time and effort needed to develop a chem-Ab. Multiple Ab-programming agents (PAs) 4a-e could be prepared rapidly using the Cu-catalyzed alkyne-azide coupling (Cu-AAC) reaction of an α5β1 inhibitor 2 with multiple linkers 3a-e, either before or after conjugating the linkers into Ab 38C2 binding sites. In these two-steps processes, the products after step 1 can be used in the next step without performing an extensive purification or analysis of the Ab-PAs or Ab-linker conjugates affording chem-Abs 38C2-(4a-e). Flow cytometry assay was used to determine the binding of the chem-Abs to U87 human glioblastoma cells expressing α5β1 integrin and identify 38C2-3e as the strongest binder. Further studies revealed that 38C2-3e strongly inhibited proliferation of U87 cells and tube formation of HUVEC in the matrigel assay, as well as tumor growth and metastasis of 4T1 cells in vivo.

• Authors: Rajib K Goswami, Yuan Liu, Cheng Liu, Richard A Lerner, Subhash C Sinha
• Journal: Molecular pharmaceutics (Mol Pharm) Vol. 10 Issue 2 Pg. 538-43 (Feb 04 2013) ISSN: 1543-8392 [Electronic] United States
• PMID: 23102054 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• Immunoglobulin Fab Fragments
• Integrin alpha5beta1
• antibody aldolase
• Fructose-Bisphosphate Aldolase

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Flow Cytometry
• Fructose-Bisphosphate Aldolase (chemistry)
• Humans
• Immunoglobulin Fab Fragments (chemistry)
• Integrin alpha5beta1 (antagonists & inhibitors)