Abstract
The limited localization and penetration of monoclonal antibodies (mAb) into solid tumors restricts their antitumor efficacy. Here, we describe a solid tumor-targeting antibody with enhanced tumor penetration activity. We designed a 22-residue peptide (A22p), which was extracted from the C-terminal basic region of semaphorin 3A (Sema3A) but modified to have higher affinity with neuropilin receptors (NRP), and genetically fused it to the C-terminus of Fc of human immunoglobulin G1 via a 15-residue (G4S)3 linker, generating Fc-A22p, for the bivalent binding to NRPs. In contrast to Fc or the monovalent A22p peptide alone, Fc-A22p homed to tumor vessels and induced vascular permeability through VE-cadherin downregulation and penetrated tumor tissues by interacting with NRPs in mice bearing human tumor xenografts. We extended the Fc-A22p platform by generating mAb-A22p antibodies of two clinically approved solid tumor-targeting mAbs, the anti-EGF receptor mAb cetuximab (erbitux), and the anti-Her2 mAb trastuzumab (herceptin). The mAb-A22p antibodies retained the intrinsic antigen binding, natural Fc-like biophysical properties, and productivity in mammalian cell cultures, comparable with those of the parent mAbs. In mouse xenograft tumor models, the mAb-A22p antibodies more efficiently homed to tumor vessels and spread into the extravascular tumor parenchyma, which significantly enhanced antitumor efficacy compared with the parent mAbs. Our results suggest that mAb-A22p is a superior format for solid tumor-targeting antibodies due to its enhanced tumor tissue penetration and greater antitumor efficacy compared with conventional mAbs.
Highlights
Poor localization and penetration of monoclonal antibodies into solid tumors is one of main mechanisms of limiting tumor response to antibody therapy [1, 2]
We demonstrated that administration of these 2 monoclonal antibodies (mAb) as mAb-a 22-residue peptide (A22p) antibodies improved tumor tissue penetration and antitumor efficacy in xenograft tumor models compared with the parent mAbs, providing a superior antibody format for solid tumor therapy
We report the development of a superior solid tumor–targeting antibody format, mAb-A22p, by genetic fusion of high-affinity neuropilin receptors (NRP)-targeting A22p peptide to the C-terminus of heavy chain of the conventional mAbs
Summary
Poor localization and penetration of monoclonal antibodies (mAb) into solid tumors is one of main mechanisms of limiting tumor response to antibody therapy [1, 2]. For anticancer mAbs targeting antigens expressed on solid tumors, systemically administered mAbs need to selectively localize to tumor vessels, cross the blood vessels into the tumor parenchyma, and penetrate into tumor tissues across the interstitium by diffusion or convection to reach as Authors' Affiliations: 1Department of Molecular Science and Technology, Ajou University; 2Department of Anatomy, Ajou University School of Medicine, Suwon; 3Antibody Engineering Team, Mogam Biotechnology Research Institute, Yongin; and 4Molecular Imaging and Therapy Branch, National Cancer Center, Goyang, Korea. The intrinsic properties of mAbs, including the relatively large size (approximately 150 kDa) and high-affinity antigen binding, may restrict vascular extravasation and transport within tumor tissue [3, 5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
