Monoclonal Antibodies for Targeted Fluorescence-Guided Surgery: History
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Due to their specificity, monoclonal antibodies have significantly impacted cancer patients’ care, becoming one of the fastest-growing classes of new drugs approved for the treatment of solid tumors. Targeted fluorescence-guided surgery is a novel technology to better visualize tumor residuals intraoperatively. It consists of a fluorescent molecular probe, that, once injected, lights up the neoplastic cells during the surgical resection. In this regard, the development of an off-the-shelf large-scale production of clinically approved, fluorescently labeled monoclonal antibodies for targeted fluorescence-guided surgery is becoming an urgent need for oncological surgeons working in this field.

  • monoclonal antibodies
  • targeted fluorescence-guided surgery
  • solid malignancies
  • surgical oncology
  • fluorophores

1. Introduction

Due to their target specificity and immunomodulatory properties, monoclonal antibodies (mAbs) have significantly impacted cancer patients’ care, becoming one of the fastest growing groups of new drugs approved for the cure of solid tumors [1]. mAbs have been effectively used to elicit long-lasting effector responses against solid malignancies by exploiting their unique capability of directly killing cancer cells while simultaneously activating the host immune system [1]. As a form of radioimmunotherapy, mAbs have also been adopted to selectively deliver high doses of radiation to tumor cells while also reducing the exposure of the surrounding healthy tissues, thus enhancing the efficacy of standard radiotherapy while minimizing its side effects [2].
Recently, fluorescently labeled mAbs have been used in the operating theatre to help surgeons better visualize and remove solid tumors in real time. This has been a revolution in the field of targeted fluorescence-guided surgery (T-FGS). Even if the adoption of fluorescently labeled mAbs in surgical oncology is still in its infancy, its applications are growing fast, with real potential to revolutionize the surgical field [3,4,5,6,7,8,9,10]. In this regard, the development of an “off-the-shelf” large-scale production of clinically approved fluorescently labeled mAbs is becoming an urgent need for oncological surgeons working in this surgical field.

2. Fluorescence-Guided Surgery (FGS): Non-Specific and Monoclonal Antibody (mAb)-Targeted

FGS is an emerging imaging tool that permits surgeons to identify healthy and pathological tissues, in real time, by intravenously delivering non-specific fluorophores (e.g., indocyanine green (ICG), 5-aminolevulinic acid, or fluorescein sodium) or fluorescently labeled molecules with a particular tissue or tumor tropism (e.g., mAbs). Depending on their route of administration, systemically administered non-specific fluorescent dyes can be used to help surgeons identify blood, bile, and lymphatic vessels during surgery, bridging the gap existing between preoperative anatomical imaging and patient-specific surgical findings [11,12].
In the surgical oncology field, non-specific dyes could be employed to distinguish neoplastic lesions from the surrounding normal tissues, by exploiting the enhanced permeability and retention (EPR) effects caused by the leaky nature of tumor vessels and the compromised lymphatic drainage [3,4,5,6,7,8,9]. Unfortunately, non-specific dyes are often unable to cause tumors from a diverse range of cancer types to fluoresce effectively as the EPR effect is not homogenous or reliable.
Besides non-specific fluorescent dyes, fluorophores have been conjugated to mAbs to deliver T-FGS, thus enhancing the intraoperative visualization of cancer at the tumor margins, loco-regional lymph nodes, and occult disease with high resolution and deep tissue penetration. By binding to a specific site of the tumor antigen (i.e., epitope), fluorescently labeled mAbs can be administered a few days before surgery, and then visualized using new-generation near-infrared (NIR) camera systems for endoscopic and open-field procedures [3,4,5,6,7,8,9].
Building on the widespread use of non-specific FGS and ICG, biomedical device companies have developed several NIR fluorescence platforms, which can be used to detect mAb-based FGS [3,4,5,8]. Briefly, the fluorophore-conjugated mAb needs to be excited at a specific wavelength to produce an invisible light, which will be collected at a set wavelength range to be transformed into an image. For surgical indications, mAbs have been conjugated to NIR dyes (e.g., IRDye800CW; wavelengths: 650–900 nm), which provide low absorption in healthy tissue, high tumor-to-background-ratio (TBR) and tissue penetration, with low interference from intrinsic fluorescence, especially when compared to the visible light spectrum (wavelengths: 400–600 nm). By doing so, the non-specific tissue background can be minimized while the tumor cells can be illuminated in real-time helping surgeons with better visualization [3,4,5,6,7,8,9].

3. Monoclonal Antibodies (mAbs) Clinically Approved for the Treatment of Extra-Hematological Solid Malignancies under Evaluation in Clinical Trials for T-FGS Purposes

In this section, mAbs clinically approved for the treatment of extra-hematological solid malignancies are summarized in Table 1 and Table 2.
Table 1. Monoclonal antibodies (mAbs) clinically approved for the treatment of solid extra-hematological malignancies.
Table 2. Monoclonal antibodies (mAbs) conjugated to the near-infrared I (NIR-I) fluorescent dye IRDye800CW for the intraoperative imaging of solid extra-hematological malignancies.

This entry is adapted from the peer-reviewed paper 10.3390/cancers16051045

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