Abstract
BackgroundFor the targeted therapy of solid tumor mediated by monoclonal antibody (mAb), there have different models of rebuilding small antibodies originated from native ones. Almost all natural antibody molecules have the similar structure and conformation, but those rebuilt small antibodies cannot completely keep the original traits of parental antibodies, especially the reduced specificity, which gravely influences the efficacy of small antibodies.MethodsIn this study, authors developed a novel mimetic in the form of VHFR1C-10-VHCDR1-VHFR2-VLCDR3-VLFR4N-10for a parental mAb induced with human breast cancer, and the mimetic moiety was conjugated to the C-terminal of toxicin colicin Ia. The novel fusion peptide, named protomimecin (PMN), was administered to MCF-7 breast cancer cells to demonstrate its killing competency in vitro and in vivo.ResultsCompared with original antibody-colicin Ia (Fab-Ia) and single-chain antibody-colicin Ia (Sc-Ia) fusion proteins, PMN retained the targeting specificity of parental antibody and could specifically kill MCF-7 cells in vitro. By injecting intraperitoneally into BALB/c athymic mice bearing MCF-7 tumors, with reduced affinity, PMN significantly suppressed the growth of tumors compared with control mice treated by toxicin protein, Fab-Ia protein, Sc-Ia protein or by PBS (p < 0.05).ConclusionThis novel mimetic antibody retained original specificity of parental antibody, and could effectively guide killer moiety to suppress the growth of breast cancer by targeted cell death.
Highlights
For the targeted therapy of solid tumor mediated by monoclonal antibody, there have different models of rebuilding small antibodies originated from native ones
Production and purification of PMN Plasmids containing the colicin Ia gene and the reversed direction immunity protein gene of wild type colicin Ia (wt Ia) protein were used to conjugate signal-moiety with wt Ia (Fig. 1c)
We introduced a new model of reconstructing small antibody for targeted therapy of solid tumors, considering that the proper complementarity-determining regions (CDRs) loops could not automatically form in the medium without the constraint force, which made the working conformation for the antigen-antibody interaction could not maintained [18]
Summary
For the targeted therapy of solid tumor mediated by monoclonal antibody (mAb), there have different models of rebuilding small antibodies originated from native ones. Antigen recognition by intact antigen-binding fragment (Fab) of immunoglobulin (Ig) is synergistically produced by all six CDRs in both VH and VL domain, CDR3 is located in the center of the antigen-recognition interface of the parental antibody and should be contained within the internal portion of the small antibody [12] Another CDR domain selected was VHCDR1 normally the closest to CDR3, which formed the synergistic interface with CDR3 for antigen-recognition [8,9]. VLFR4N-10 and VHFR2 supported CDR3 to form the projected loop conformation, and the VHCDR1 loop was restrained on both sides by VHFR2 and VHFR1C-10 forming the other loop conformation These selected components of the mimetic are original and not changed or substituted from the parental antibody. We proposed that the construct of mimetic kept specificity similar to that of parental antibody (Fig. 1a)
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