Synergistic anti-tumor therapy by a comb-like multifunctional antibody nanoarray with exceptionally potent activity.

Huafei Li,Fulei Zhang,Ge Zhang,Cheng Jiang,Li Zhang,Mengxin Zhao,Xiandi Zhu,Wei Li,Huafeng Wei,He Zhao,Yun Sun,Changhong Ke,Di Chen

doi:10.1038/srep15712

Abstract

Simultaneously blocking multiple mediators offers new hope for the treatment of complex diseases. However, the curative potential of current combination therapy by chronological administration of separate monoclonal antibodies (mAbs) or multi-specific mAbs is still moderate due to inconvenient manipulation, low cooperative effectors, poor pharmacokinetics and insufficient tumor accumulation. Here, we describe a facile strategy that arms distinct mAbs with cooperative effectors onto a long chain to form a multicomponent comb-like nano mAb. Unlike dissociative parental mAbs, the multifunctional mAb nanoarray (PL-RB) constructed from type I/II anti-CD20 mAbs shows good pharmacokinetics. This PL-RB simultaneously targets distinct epitopes on a single antigen (Ag) and neighboring Ags on different lymphocytes. This unique intra- and intercellular Ag cross-linking endows the multifunctional mAb nanoarray with potent apoptosis activity. The exceptional apoptosis, complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) that are synchronously evoked by the nano PL-RB are further synergistically promoted via enhanced permeability and retention (EPR), which resulted in high intratumor accumulation and excellent anti-lymphoma efficiency.

Highlights

Accumulation in normal organs and the quick exhaustion of complements, resulting in undesirable side effects and low antibody-dependent cellular cytotoxicity (ADCC) and CDC27–29
The high molecular weight (Mw) PL-RB nano-array was confirmed by SDS-PAGE (Fig. 2a)
As illustrated in S1, the average number of mAbs along one polymer chain is larger than 100. This is very important because the larger the nanoarray is, the better the efficiency will be. This nanoarray with large MW was further tested by dynamic laser light scattering (LLS)

Summary

Introduction

Accumulation in normal organs and the quick exhaustion of complements, resulting in undesirable side effects and low ADCC and CDC27–29. Most importantly, grouping different types of mAbs onto a single long chain to form a comb-like nano mAb array, that is, the nano mAbs can simultaneously target distinct epitopes on a single antigen or on neighboring antigens, or touch different epitopes on different cells. This unique intra-/intercellular antigen cross-linking may evoke some unexpected cytotoxicity, such as apoptosis. The nano-based mAbs with synergistic effects may represent a new generation of multifunctional mAbs. In this study, the classical type I and type II anti-CD20 antibodies, which target distinct epitopes of the CD20 molecule, are sampled and facilely armed to a long polymer chain to form a novel, multifunctional comb-like anti-CD20 mAb nanoarray (PL-RB). The in vivo synergic antitumor activity of PL-RB is systemically investigated in disseminated and localized xeno-transplant human NHL models

Methods

Results

Conclusion