Development of therapeutic monoclonal antibodies against DKK1 peptide-HLA-A2 complex to treat human cancers

Sep 21, 2026

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Targeted immunotherapy with monoclonal antibodies (mAbs) offers an effective and safe approach for treating malignancies, yet new targets and improved cytotoxic mechanisms remain active research goals. This study evaluates DKK1 as an immunotherapy target and develops DKK1-A2 mAbs recognizing DKK1 P20 peptide presented by HLA-A*0201. The antibodies induce caspase-9–mediated apoptosis, promote CDC and ADCC, and show therapeutic activity in xenograft mouse models while exhibiting limited off-target binding and toxicity.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages17

Reading Time43 min

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ABSTRACT

Background

Methods

Results

Conclusion

WHAT IS ALREADY KNOWN ON THIS TOPIC

WHAT THIS STUDY ADDS

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

INTRODUCTION

Open access To cite: Qian J, Wang Q, Xiao L, et al. Development of therapeutic monoclonal antibodies against DKK1 peptide-HLA-A2 complex to treat human cancers. Journal for ImmunoTherapy of Cancer 2024;12:e008145 . doi:10 . 1136/ jitc-2023-008145 ► Additional supplemental material is published online only. To view, please visit the journal online ([http://dx.doi.org/10](http://dx.doi.org/10) . 1136/jitc-2023-008145) . Accepted 11 January 2024 © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. 1Center for Translational Research in Hematological Malignancies, Houston Methodist Neal Cancer Center/ Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX, USA 2Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA 3Department of Pathology and Genomic Medicine, Institute for Academic Medicine, Houston Methodist Research Institute, Houston, TX, USA Correspondence to Dr Qing Yi; [qyi@houstonmethodist.org](qyi@houstonmethodist.org) Original research Development of therapeutic monoclonal antibodies against DKK1 peptideHLA-A2 complex to treat human cancers Jianfei Qian,1 Qiang Wang,1 Liuling Xiao,1 Wei Xiong ,1 Miao Xian,1 Pan Su,1 Maojie Yang,1 Chuanchao Zhang,1 Yabo Li,1 Ling Zhong,1 Siddhartha Ganguly,2 Youli Zu,3 Qing Yi 1 ABSTRACT Background Targeted immunotherapy with monoclonal antibodies (mAbs) is an effective and safe method for the treatment of malignancies. Development of mAbs with improved cytotoxicity, targeting new and known tumor-associated antigens, therefore continues to be an active research area. We reported that Dickkopf-1 (DKK1) is a good target for immunotherapy of human cancers based on its wide expression in different cancers but not in normal tissues. As DKK1 is a secreted protein, mAbs binding directly to DKK1 have limited effects on cancer cells in vivo. Methods The specificity and antibody-binding capacity of DKK1-A2 mAbs were determined using indirect ELISA, confocal imaging, QIFIKIT antibody-binding capacity and cell surface binding assays. The affinity of mAbs was determined using a surface plasmon resonance biosensor. A flow cytometry-based cell death was performed to detect tumor cell apoptosis. Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays were used to evaluate the ability of DKK1-A2 mAbs to mediate ADCC and CDC activities against tumor cells in vitro. Flow cytometry data were collected with an FACSymphony A3 cell analyzer and analyzed with FlowJo V.10.1 software. Human cancer xenograft mouse models were used to determine the in vivo therapeutic efficacy and the potential safety and toxicity of DKK1-A2 mAbs. In situ TUNEL assay was performed to detect apoptosis in tumors and mouse organs. Results We generated novel DKK1-A2 mAbs that recognize the DKK1 P20 peptide presented by human HLA-A*0201 (HLA-A2) molecules (DKK1-A2 complexes) that are naturally expressed by HLA-A2+DKK1+ cancer cells. These mAbs directly induced apoptosis in HLAA2+DKK1+ hematologic and solid cancer cells by activating the caspase-9 cascade, effectively lysed the cancer cells in vitro by mediating CDC and ADCC and were therapeutic against established cancers in their xenograft mouse models. As DKK1 is not detected in most human tissues, DKK1-A2 mAbs neither bound to or killed HLA-A2+ blood cells in vitro nor caused tissue damage in tumor-free or tumor-bearing HLA-A2-transgenic mice. Conclusion Our study suggests that DKK1-A2 mAbs may be a promising therapeutic agent to treat human cancers. WHAT IS ALREADY KNOWN ON THIS TOPIC | ⇒ Dickkopf-1 (DKK1) is a good target for immunotherapy of human cancers based on its wide expression in different cancers but not in normal tissues.
⇒ As DKK1 is a secreted protein, mAbs binding directly to DKK1 have limited effects on cancer cells in vivo.
WHAT THI

FAQs

What therapeutic target does the study focus on for human cancers?

The study focuses on Dickkopf-1 (DKK1) and develops mAbs against the DKK1 P20 peptide presented by HLA-A*0201 (HLA-A2) molecules.

How do DKK1-A2 monoclonal antibodies affect cancer cells in vitro?

They directly induce apoptosis in HLA-A2+DKK1+ cancer cells via activation of the caspase-9 cascade and effectively lyse cancer cells through CDC and ADCC activities.

Do the DKK1-A2 antibodies show safety concerns in models with HLA-A2 expression?

The study reports that DKK1-A2 mAbs neither bind to nor kill HLA-A2+ blood cells in vitro and do not cause tissue damage in tumor-free or tumor-bearing HLA-A2-transgenic mice.

Sep 21, 2026

Uploaded by Logic