Development of a Bispecific Antibody Targeting CD30 and CD137 on Hodgkin and Reed-Sternberg Cells

Yating Li,Evelyn Ngoh,Herbert Schwarz,Cheng-I Wang,Hiu Yi Wong,Sakthi Rajendran,Man Si Cheng

doi:10.3389/fonc.2019.00945

Abstract

Hodgkin Lymphoma (HL) is a malignancy that frequently affects young adults. Although, there are effective treatments not every patient responds, necessitating the development of novel therapeutic approaches, especially for relapsed and refractory cases. The two TNF receptor family members CD30 and CD137 are expressed on Hodgkin and Reed Sternberg (HRS) cells, the malignant cells in HL. We found that this co-expression is specific for HRS cells. Based on this discovery we developed a bispecific antibody that binds preferentially to the CD30, CD137-double positive HRS cells. The CD30, CD137 bispecific antibody gets internalized into HRS cells opening up the possibility to use it as a carrier for a toxin. This antibody also induces antibody-dependent, cell-mediated cytotoxicity in CD30, CD137-double positive HRS cells. The enhances specificity of the CD30, CD137 bispecific antibody to HRS cells makes it a promising candidate for development as a novel HL treatment.

Highlights

Hodgkin Lymphoma (HL) is a hematological malignancy that affects elderly but a significant number of young adults
CD137 is expressed by Hodgkin and Reed Sternberg (HRS) cells of 86% of classical HL tumor samples [10, 11]
There is a clear co-localization of CD30 and CD137 on giant cells, confirming co-expression of the two molecules on HRS cells

Summary

Introduction

Hodgkin Lymphoma (HL) is a hematological malignancy that affects elderly but a significant number of young adults. For 2018, there are an estimated 8,260 new cases of HL and 1,070 deaths due to HL in the USA alone [1]. Most HL patients respond well to conventional chemotherapy, relapses occur in around in 10 and 40% of early stage and late stage cases, respectively [2]. High dose chemotherapy and autologous stem cell transplantation may help those patients but these treatments are associated with significant morbiditiy and mortality [3]. With the emergence of checkpoint inhibitors, the objective response rates of HL has improved to above 60% [4]. About 2% of patients fail to respond and about 13% will relapse after initial treatment [5]

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