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Development and characterization of a novel anti-OX40 antibody for potent immune activation

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

With the great success of anti-CTLA-4 and anti-PD-1 therapeutics in cancer immunotherapy, tumor necrosis factor receptor superfamily members have been recognized as ideal targets to provide co-stimulatory signals in combination with immune checkpoint blocking antibodies. Among these is OX40 (CD134), a co-stimulatory molecule expressed by activated immune cells. Recently, several anti-OX40 agonistic monoclonal antibodies, pogalizumab as the most advanced, have entered early phase clinical trials. Using a yeast platform and multiple screening methods, we identified a fully human anti-OX40 antibody (IBI101) with distinct modes of action. Unlike pogalizumab, IBI101 partially blocks the binding of OX40 to its ligand OX40L and exhibits both FcγR-dependent and independent agonistic activities in NF-κB luciferase reporter assays. IBI101 also promotes T cell activation and proliferation in vitro. These unique properties partially explain the more potent anti-tumor activity of IBI101 than that of pogalizumab in humanized NOG mice bearing LoVo tumors. In addition, IBI101 shows efficacious anti-tumor activity in mice when administrated alone or in combination with anti-PD-1 antibodies. In human OX40 knock-in mice bearing MC38 colon carcinoma, IBI101 treatment induces tumor antigen-specific CD8+ T-cell responses, decreases immunosuppressive regulatory T cells in tumor, and enhances the immune response to PD-1 inhibition. Preclinical studies of IBI101 in non-human primates demonstrate typical pharmacokinetic characteristics of an IgG antibody and no drug-related toxicity. Collectively, IBI101 has desirable preclinical attributes which support its clinical development for cancer treatment.

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Abbreviations

IBI101:

A fully human anti-OX40 antibody

ATCC:

American type culture collection

OX40L:

CD252 or OX40 ligand

IL-2:

Interleukin 2

NF-κB:

Nuclear factor (NF)-kappaB

POGA:

Pogalizumab

TNFR Family:

The tumor necrosis factor receptor family

Teff:

T effector cells

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Acknowledgements

The authors would like to thank Dr. Pu Pu and Dr. Siyi Hu for their helpful suggestions during manuscript preparation.

Funding

This study was supported by the National Key Research and Development Program of China (2017YFC0909801).

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Author notes

  1. Zhihui Kuang and Hua Jing contributed equally to this work.

Authors and Affiliations

  1. Innovent Biologics (Suzhou) Co., Ltd, 168 Dongping Street, Suzhou Industrial Park, Suzhou, 215123, Jiangsu, China

    Zhihui Kuang, Hua Jing, Zhihai Wu, Jie Wang, Yiming Li, Haiqing Ni, Pan Zhang, Weiwei Wu, Min Wu, Shuaixiang Zhou, Xuan Qiu, Dongdong Wu, Bingliang Chen, Michael Yu & Junjian Liu

  2. Adimab LLC., 7 Lucent Drive, Lebanon, NH, 03766, USA

    Bianka Prinz & Hemanta Baruah

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  1. Zhihui Kuang
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Contributions

HJ, BC, MY, and JL designed the study; ZK, HN, ZW, SZ and YL performed the in vitro experiments; JW, MW, PZ and WW performed the experiment in rodent, XQ and DW performed the experiment in primate. BP and HB provided the yeast platform. HJ and ZK wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Junjian Liu.

Ethics declarations

Conflict of interest

Bianka Prinz and Hemanta Baruah have no potential conflicts of interest to disclose. All other authors are employees of Innovent Biologics (Suzhou).

Ethical approval and ethical standards

All mice experiments were performed in accordance with regulations for care and use of laboratory animals at Innovent Biologics and were approved by Innovent’s Institutional Animal Care and Use Committee (IACUC-01). All monkey experiments were approved by IACUC and performed according to the regulation of AAALAC.

Animal source

NOG mice were purchased from Beijing Vital River Laboratory Animal Technology Co. (Beijing, China). OX40 knock in mice were purchased from Shanghai Model organisms (Shanghai, China). Cynomolgus monkey were purchased from Beijing Prima Biotech Inc.

Cell line authentication

RAJI, Jurkat, HEK293 and Lovo cell lines were obtained from ATCC (Manassas, VA). CHO-S cell line was obtained from Themo Fisher Scientific, Carlsbad, CA, USA). MC38 cell line was obtained from Shanghai Model Organisms Center, Inc. (Shanghai, China). Peripheral Blood Mononuclear Cells cells were purchased from Allcells (Alameda, CA, USA).

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Kuang, Z., Jing, H., Wu, Z. et al. Development and characterization of a novel anti-OX40 antibody for potent immune activation. Cancer Immunol Immunother 69, 939–950 (2020). https://doi.org/10.1007/s00262-020-02501-2

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  • DOI: https://doi.org/10.1007/s00262-020-02501-2

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