The state of the art of bispecific antibodies for treating human malignancies

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Abstract

Bispecific antibodies (bsAb) that target two independent epitopes or antigens have been extensively explored in translational and clinical studies since they were first developed in the 1960s. Many bsAbs are being tested in clinical trials for treating a variety of diseases, mostly cancer. Here, we provide an overview of various types of bsAbs in clinical studies and discuss their targets, safety profiles, and efficacy. We also highlight the current challenges, potential solutions, and future directions of bsAb development for cancer treatment.

Abstract

In this review, N. Li, Y. Nie & colleagues provide an overview of the current clinical development and future directions of bi‐specific antibodies for cancer treatment.

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Most cited references 90

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Molecular mechanisms of T cell co-stimulation and co-inhibition.

Lieping Chen, Dallas Flies (2013)

Co-stimulatory and co-inhibitory receptors have a pivotal role in T cell biology, as they determine the functional outcome of T cell receptor (TCR) signalling. The classic definition of T cell co-stimulation continues to evolve through the identification of new co-stimulatory and co-inhibitory receptors, the biochemical characterization of their downstream signalling events and the delineation of their immunological functions. Notably, it has been recently appreciated that co-stimulatory and co-inhibitory receptors display great diversity in expression, structure and function, and that their functions are largely context dependent. Here, we focus on some of these emerging concepts and review the mechanisms through which T cell activation, differentiation and function is controlled by co-stimulatory and co-inhibitory receptors.

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4-1BB Costimulation Ameliorates T Cell Exhaustion Induced by Tonic Signaling of Chimeric Antigen Receptors

Adrienne H Long, Waleed M. Haso, Jack F. Shern … (2015)

Chimeric antigen receptors (CARs) targeting CD19 have mediated dramatic anti-tumor responses in hematologic malignancies, but tumor regression has rarely occurred using CARs targeting other antigens. It remains unknown whether the impressive effects of CD19 CARs relate to greater susceptibility of hematologic malignancies to CAR therapies, or superior functionality of the CD19 CAR itself. We discovered that tonic CAR CD3ζ phosphorylation, triggered by antigen-independent clustering of CAR scFvs, can induce early exhaustion of CAR T cells that limits anti-tumor efficacy. Such activation is present to varying degrees in all CARs studied, with the exception of the highly effective CD19 CAR. We further identify that CD28 costimulation augments, while 4-1BB costimulation ameliorates, exhaustion induced by persistent CAR signaling. Our results provide biological explanations for the dramatic anti-tumor effects of CD19 CARs and for the observations that CD19.BBz CAR T cells are more persistent than CD19.28z CAR T cells in clinical trials.

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Is Open Access

Cytokine release syndrome

Alexander Shimabukuro-Vornhagen, Philipp Gödel, Marion Subklewe … (2018)

During the last decade the field of cancer immunotherapy has witnessed impressive progress. Highly effective immunotherapies such as immune checkpoint inhibition, and T-cell engaging therapies like bispecific T-cell engaging (BiTE) single-chain antibody constructs and chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in clinical trials and some of these agents have already received regulatory approval. However, along with growing experience in the clinical application of these potent immunotherapeutic agents comes the increasing awareness of their inherent and potentially fatal adverse effects, most notably the cytokine release syndrome (CRS). This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors. In addition, based on the current evidence we give practical guidance to the management of the cytokine release syndrome.

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Author and article information

Contributors

Yingjie Nie:

ORCID: https://orcid.org/0000-0002-8337-5304

nienyj@hotmail.com

Ning Li:

ORCID: https://orcid.org/0000-0002-3945-2536

Lining@cicams.ac.cn

Journal

Journal ID (nlm-ta): EMBO Mol Med

Journal ID (iso-abbrev): EMBO Mol Med

Journal ID (doi): 10.1002/(ISSN)1757-4684

Journal ID (publisher-id): EMMM

Journal ID (hwp): embomm

Title: EMBO Molecular Medicine

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 1757-4676

ISSN (Electronic): 1757-4684

Publication date (Electronic): 24 August 2021

Publication date (Print): 07 September 2021

Volume: 13

Issue: 9 ( doiID: 10.1002/emmm.v13.9 )

Electronic Location Identifier: e14291

Affiliations

[ ¹ ] Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China

[ ² ] NHC Key Laboratory of Pulmonary Immunological Diseases is supported by the non‐profit Central Research Institute fund of Chinese Academy of Medical Sciences (2019PT320003) Guizhou Provincial People’s Hospital Guiyang China

[ ³ ] Excyte Biopharma Ltd Beijing China

[ ⁴ ] Excyte LLC Rockville MD USA

[ ⁵ ] Nanjing Umab‐biopharma Co., Ltd Nanjing China

[ ⁶ ] Hangzhou Genekine Biotech Co., Ltd Hangzhou China

[ ⁷ ] Department of Medical Oncology Harbin Medical University Cancer Hospital Harbin China

[ ⁸ ] Queen Mary School Nanchang University Nanchang China

[ ⁹ ] Geneplus Shenzhen China

[ ¹⁰ ] China Pharmaceutical University Nanjing China

Author notes

[*] [* ] Corresponding author. Tel: +86 13639043101; E‐mail: nienyj@ 123456hotmail.com

**Corresponding author. Tel: +86 010 87788713; E‐mail: Lining@ 123456cicams.ac.cn

[ † ]

These authors contributed equally to this work

Author information

Kun Chen https://orcid.org/0000-0002-1855-5149

Qi Lei https://orcid.org/0000-0003-1953-9236

Andy Qingan Yuan https://orcid.org/0000-0001-6200-2544

Yingjie Nie https://orcid.org/0000-0002-8337-5304

Ning Li https://orcid.org/0000-0002-3945-2536

Article

Publisher ID: EMMM202114291

DOI: 10.15252/emmm.202114291

PMC ID: 8422067

PubMed ID: 34431224

SO-VID: da36eb05-9462-41b9-8983-49088c6ffbd1

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date revision received : 08 July 2021

Date received : 18 March 2021

Date accepted : 09 July 2021

Page count

Figures: 5, Tables: 1, Pages: 11, Words: 9731

Funding

Funded by: Chinese Academy of Medical Sciences , doi 10.13039/501100005150;

Award ID: 2019XK320068

Funded by: Beijing Municipal Science and Technology Commission (International Pharmaceutical Clinical Research and Development Platform 2015) , doi 10.13039/501100009592;

Funded by: Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (Platform Improvement of Clinical Trial Capability 2020‐I2M‐2‐007)

Funded by: Beijing Municipal Health Commission, Beijing Demonstration Research Ward

Award ID: BCRW20200303

Funded by: Cancer Foundation of China (PLATFORM Study of Precision Medicine for Rare Tumors)

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source-schema-version-number 2.0

cover-date 07 September 2021

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.7 mode:remove_FC converted:07.09.2021

ScienceOpen disciplines: Molecular medicine

Keywords: bispecific antibodies (bsab),malignancies,single‐chain variable fragment (scfvs),tumor associate antigen,tumor‐specific antigen,cancer,immunology

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: bispecific antibodies (bsab), malignancies, single‐chain variable fragment (scfvs), tumor associate antigen, tumor‐specific antigen, cancer, immunology

The state of the art of bispecific antibodies for treating human malignancies

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Abstract

Abstract

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Cancer Immunotherapy

Most cited references 90

Molecular mechanisms of T cell co-stimulation and co-inhibition.

4-1BB Costimulation Ameliorates T Cell Exhaustion Induced by Tonic Signaling of Chimeric Antigen Receptors

Cytokine release syndrome

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