A fully human CXCR4 antibody demonstrates diagnostic utility and therapeutic efficacy in solid tumor xenografts

Abstract

For physiologically important cancer therapeutic targets, use of non-invasive imaging for therapeutic guidance and monitoring may improve outcomes for treated patients. The CXC chemokine receptor 4 (CXCR4) is overexpressed in many cancers including non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). CXCR4 overexpression contributes to tumor growth, progression and metastasis. There are several CXCR4-targeted therapeutic agents currently in clinical trials. Since CXCR4 is also crucial for normal biological functions, its prolonged inhibition could lead to unwanted toxicities. While CXCR4-targeted imaging agents and inhibitors have been reported and evaluated independently, there are currently no studies demonstrating CXCR4-targeted imaging for therapeutic guidance.

Monoclonal antibodies (mAbs) are commonly used for cancer therapy and imaging. Here, an ⁸⁹Zr-labeled human CXCR4-mAb (⁸⁹Zr-CXCR4-mAb) was evaluated for detection of CXCR4 expression with positron emission tomography (PET) while its native unmodified analogue was evaluated for therapy in relevant models of NSCLC and TNBC. In vitro and in vivo evaluation of ⁸⁹Zr-CXCR4-mAb showed enhanced uptake in NSCLC xenografts with a high expression of CXCR4. It also had the ability to detect lymph node metastases in an experimental model of metastatic TNBC. Treatment of high and low CXCR4 expressing NSCLC and TNBC xenografts with CXCR4-mAb demonstrated a therapeutic response correlating with the expression of CXCR4. Considering the key role of CXCR4 in normal biological functions, our results suggest that combination of ⁸⁹Zr-CXCR4-mAb-PET with non-radiolabeled mAb therapy may provide a precision medicine approach for selecting patients with tumors that are likely to be responsive to this treatment.