2D) and EGFR FD increased (Fig. in line with many preclinical reports, but also quantified the extent of inter-patient, inter-tumor, and intra-tumor heterogeneity of antibody delivery. This study demonstrated the strong predictive value of tumor size for intratumoral antibody accumulation and its significant impact on antibody distribution in both main tumor and lymph node metastasis. Furthermore, this study established the feasibility of using contrast-enhanced MRI to predict antibody delivery. Conclusions: This study provides a clinically translatable platform to measure antibody delivery into solid tumors and yields valuable insight Glucagon HCl into clinically relevant antibody tumor penetration, with implications in the selection of patients amenable to antibody therapy and the design of more effective dosing strategies. Keywords: antibody delivery, head and neck cancers, fluorescence, MRI, early-phase clinical trial Introduction Heterogeneous individual response to antibody-based therapeutics remains a major challenge in drug discovery and individual care, especially in oncology and immune therapy (1,2). Although genomics is usually sought to predict therapeutic response, limited success has been achieved (3). An important but often neglected aspect is the measurement of intratumoral antibody concentration and distribution (4,5), which could guideline precision dosing and select patients with high drug accumulation and thus more likely to respond to therapies (6C8). Current early phase clinical trials routinely use plasma drug concentrations as a surrogate to guide dose optimization (9,10), which assumes homogenous intratumoral antibody distribution and may lead to suboptimal response and resistance (5). Therefore, quantification and prediction of intratumoral antibody delivery remain a critically unmet need in the medical center. Since understanding variability and biological correlates of antibody delivery in humans are not a part of drug development routine, our current knowledge on intratumoral antibody distribution and the underlying biological mechanism has largely originated from preclinical studies (4,11C18), which has shown low and heterogeneous antibody delivery into solid tumors. To be effective, systemic anti-cancer brokers must extravasate across blood vessels and diffuse through the interstitial space before binding to Glucagon HCl its cellular target in optimal concentrations. Based on this biophysical process, preclinical studies have hypothesized several barriers to drug transport, including reduced vascular density and disorganized vascular architecture (4,19), complex composition and structure of the extracellular matrix (20,21), antigen expression levels (22,23), and sub-optimal antibody dosing (24). Given the large space between preclinical efficacies of antibodies and the clinical outcomes (25,26), it is imperative to directly measure antibody delivery and verify these hypothesis in human patients. Glucagon HCl Although positron emission tomography (PET) imaging of radiolabeled antibodies is an important clinical approach to evaluate the whole-body antibody distribution at the organ level non-invasively (27C30), this approach is limited by its high cost, inevitable radiation, and insufficient resolution (1~2 mm) (27). With the introduction of fluorescently labeled antibodies under good manufacturing practice suitable for patient injection (31,32), it is now possible to use high-resolution Glucagon HCl fluorescence imaging to complement organ-level PET imaging to measure intratumoral antibody distribution and cellular antibody binding and to correlate with tumor microenvironment factors (5,27). In this study, we proposed a clinically relevant imaging and computation platform that integrated pretreatment contrast-enhanced magnetic resonance imaging (MRI) and a fluorescently labeled therapeutic antibody to measure and predict antibody delivery into solid tumors. We systemically administered an anti-epidermal growth factor receptor (EGFR) antibody (approved anti-cancer drug by the U.S. Food and Drug Administration (FDA)) conjugated with a near-infrared (NIR) fluorophore (panitumumab-IRDye800CW) into 24 patients with head and neck squamous cell carcinoma (HNSCC). Using surgical specimens from these patients, we attempted to quantify the extent of heterogeneity in antibody distribution within human tumors, to assess the impact of tumor biological parameters on intratumoral antibody delivery into human tumors, and to evaluate the feasibility of using contrast-enhanced MRI to predict antibody delivery into human solid tumors. Materials and Methods Clinical Study Overview Fig. 1 illustrated an overview of the study design. First, Rabbit polyclonal to EHHADH patients received the standard-of-care MRI scan (including the contrast-enhanced T1-weighted imaging sequence). Next, patients.

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