The inextricable axis of targeted diagnostic imaging and therapy: An immunological natural history approach

Abstract

Summary In considering the challenges of approaches to clinical imaging, we are faced with choices that sometimes are impacted by rather dogmatic notions about what is a better or worse technology to achieve the most useful diagnostic image for the patient. For example, is PET or SPECT most useful in imaging any particular disease dissemination? The dictatorial approach would be to choose PET, all other matters being equal. But is such a totalitarian attitude toward imaging selection still valid? In the face of new receptor targeted SPECT agents one must consider the remarkable specificity and sensitivity of these agents. 99mTc-Tilmanocept is one of the newest of these agents, now approved for guiding sentinel node biopsy (SLNB) in several solid tumors. Tilmanocept has a Kd of 3×10−11 M, and it specificity for the CD206 receptor is unlike any other agent to date. This coupled with a number of facts, that specific disease-associated macrophages express this receptor (100 to 150 thousand receptors), the receptor has multiple binding sites for tilmanocept (>2 sites per receptor) and that these receptors are recycled every 15 minutes to bind more tilmanocept (acting as intracellular “drug compilers” of tilmanocept into non-degraded vesicles), give serious pause as to how we select our approaches to diagnostic imaging. Clinically, the size of SLNs varies greatly, some, anatomically, below the machine resolution of SPECT. Yet, with tilmanocept targeting, the SLNs are highly visible with macrophages stably accruing adequate 99mTc-tilmanocept counting statistics, as high target-to-background ratios can compensate for spatial resolution blurring. Importantly, it may be targeted imaging agents per se, again such as tilmanocept, which may significantly shrink any perceived chasm between the imaging technologies and anchor the diagnostic considerations in the targeting and specificity of the agent rather than any lingering dogma about the hardware as the basis for imaging approaches. Beyond the elements of imaging applications of these agents is their evolution to therapeutic agents as well, and even in the neo-logical realm of theranostics. Characteristics of agents such as tilmanocept that exploit the natural history of diseases with remarkably high specificity are the expectations for the future of patient- and disease-centered diagnosis and therapy.

Mannose receptor high, M2 dermal macrophages mediate nonhealing Leishmania major infection in a Th1 immune environment

“…For example, MR plays an important role in the phagocytosis of a virulent but not an attenuated strain of Mycobacterium tuberculosis ( Schlesinger, 1993 ). Reagents that specifically target the CD206 macrophage MR in humans are being developed for diagnostic imaging and therapy to inhibit tumor progression ( Cope et al, 2016 ). The clinical relevance of our findings can be inferred from the fact that the LmSd strain was isolated from a patient with chronic lesions and persisting organisms even after treatment and despite a strong cell-mediated immune response to Leishmania antigens ( Neva et al, 1979 ).…”

Cy3‐tilmanocept labeling of macrophages in joints of mice with antibody‐induced arthritis and synovium of human patients with rheumatoid arthritis

“…Even more important for the patient is that this study portends the application of γ-tilmanocept to RA staging as it relates to pathotypical histopathology for RA and drug specificity responsiveness of RA to the RA pathotype. [43][44][45][46][47][48][49] In recent patient evaluations, Lewis et al identified transcriptional subgroups in synovium linked to three distinct RA pathotypes: fibroblastic pauci-immune pathotype, macrophage-rich diffuse-myeloid pathotype, and a lympho-myeloid pathotype characterized by infiltration of lymphocytes and myeloid cells. 48,50 This is suggestive of divergent pathogenic pathways or activation disease states.…”

Molecular Aspects and Future Perspectives of Cytokine-Based Anti-cancer Immunotherapy

“…The cells of tumor and TME secrete CCL2 and macrophage colony-stimulating factor (M-CSF) (Qian et al, 2011) and attract a large number of inflammatory monocytes to tumor sites where they differentiate into TAMs due to secretion of IL4, IL10, and IL13 (Wang and Joyce, 2010;Chuang et al, 2016). TAMs can be identified by CD163, CD200R, CD204, CD206, and HLA-DR low expression (Yang et al, 2015;Cope et al, 2016;Kubota et al, 2017). The recruited macrophages represent a significant part of the TME and provide significant support to the tumor.…”