CD89-mediated recruitment of macrophages via a bispecific antibody enhances anti-tumor efficacy

Bingyu Li,Lijun Xu,Chenyu Pi,Yanxin Yin,Kun Xie,Fei Tao,Renhao Li,Hua Gu,Jianmin Fang

doi:10.1080/2162402x.2017.1380142

Abstract

ABSTRACTSince tumors are often infiltrated by macrophages, it would be advantageous to turn these types of cells into cytotoxic effector cells. Here, we have designed a novel bispecific antibody (BsAb) that targets both tumor antigen (CD20) and the FcαRI receptor (CD89). This antibody could be used to lyse tumors by connecting tumor cells to CD89-expressing immune effector cells such as macrophages and neutrophils. Previously there were very limited attempts to exploit FcαRI-expressing cells as effector cells for tumor cell-killing, largely due to the lack of an appropriate in vivo model, since mice do not express a human CD89 homolog. In this study, we used a transgenic mouse strain with specific expression of CD89 on macrophages and monocytes. In this transgenic mouse model, the CD89 bispecific antibody showed significant anti-tumor activities, demonstrating that bispecific antibodies can redirect macrophages, including M2 macrophages, to mediate additional effector function in the tumor microenvironment. This approach realized the full potential of the innate immune system and could be applied to other tumor-associated antigens especially the solid tumors, thus has potential to translate into clinical benefits in human cancers.

Highlights

Antibodies have the potential to increase the specificity of cancer therapy by targeting selected tumor-associated antigens
Our results indicate that the CD89 bispecific antibody shows significant anti-tumor activities in the generated CD89 transgenic mouse model, demonstrating that bispecific antibodies can redirect macrophages, including M2 macrophages, to mediate additional effector functions in the tumor microenvironment
The bispecific antibody targeting CD89 and CD20 generated in this study is based on a human IgG1 isotype with heavy chains comprised of a variable VH domain and three constant domains: CH1, CH2, and CH3

Summary

Introduction

Antibodies have the potential to increase the specificity of cancer therapy by targeting selected tumor-associated antigens. Bispecific antibodies (BsAbs) have been used as potential cancer therapeutic methods for decades.[2] The anti-tumor effects of BsAbs can be divided into direct effects, such as blocking growth factors, inhibition of proliferation, or induction of apoptosis,[3] and indirect effects involving recruitment of immune effector mechanisms such as cell-mediated lysis of target cells with immunoglobulin receptors on effector cells.[4] These mechanisms are used in the therapeutic concept of bispecific antibodies; antibodies are directed to cytotoxic trigger molecules such as effector cell receptors. Many Fc receptor-expressing cells are not cytolytic for tumor cells (e.g., B cells and platelets) and some Fc receptor isoforms (e.g., FcgRIIb and FcgRIIIb) bind antibodies, but do not trigger cytolytic cascades

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