Biology subjects

Herrmann, K.

Publications and source records attributed to Herrmann, K..

3 recordsLinked to original sources

bioRxiv2024

Development of a LRRC15-Targeted Radio-Immunotheranostic Approach to Deplete Pro-tumorigenic Mechanisms and Immunotherapy Resistance

Leucine-rich repeat containing 15 (LRRC15) has emerged as an attractive biomarker and target for cancer therapy. We have developed a humanized monoclonal antibody (mAb), DUNP19, that specifically binds to a phylogenetically conserved LRRC15 epitope and is internalized by target-expressing cancer and stromal cells. In xenograft mouse models, Lutetium-177 labeled DUNP19 ([177Lu]-DUNP19) enables non-invasive imaging and precise radiotherapy to LRRC15-expressing cancer cells and murine cancer-associated fibroblasts (CAFs), halting tumor progression and prolonging survival with minimal toxicity. Transcriptomic analyses of [177Lu]-DUNP19-treated tumors reveal a loss of pro-tumorigenic mechanisms, including a transforming growth factor beta (TGF{beta})-driven and LRRC15+ signature associated with immunotherapy resistance. Together, these results demonstrate that radio-theranostic targeting of LRRC15 with DUNP19 is a compelling precision medicine platform for image-guided diagnosis, eradication, and reprogramming of LRRC15+ tumor tissue that drives immuno-resistance and aggressive disease. SIGNIFICANCEWe introduce a pioneering LRRC15-guided radio-theranostic approach integrating clinical imaging and radioimmunotherapy. Our strategy utilizes a mAb, DUNP19, to target LRRC15-expressing cancer cells and fibroblasts, demonstrating significant tumor reduction, prolonged survival, and reversal of TGF{beta}-driven treatment resistance. This approach offers a promising strategy for improving outcomes in aggressive cancers.

pharmacology and toxicology↗

bioRxiv2023

Distribution of carbon monoxide (CO) in several tissues from Atlantic bottlenose dolphins (Tursiops truncatus)

Carbon monoxide (CO) is known as "The Silent Killer" due to its toxic effect at high concentrations, leading to an impairment in oxygen storage, delivery, and use. The cytotoxicity of CO is due to its high affinity for transition metals, such as iron, where CO outcompetes oxygen for the heme binding sites on hemoproteins in the body. CO is made in vivo in most organisms as a byproduct of heme degradation via heme oxygenase enzymes. Certain species of deep-diving marine mammals with high quantities of hemoproteins in blood and skeletal muscle have naturally elevated concentrations of CO in these tissues. To date, there exist few data on extravascular tissue CO content in wild animals. This study aims to characterize CO concentrations in nine different tissues from stranded Atlantic bottlenose dolphins (Tursiops truncatus). We found three tissues (liver, skeletal muscle, and spleen) have higher CO concentrations than other tissues. In a subset of samples from animals that tested positive for dolphin morbillivirus, the CO content in their kidney and liver was lower when compared to animals that tested negative. The mean CO concentration found in every tissue from dolphins was higher than those previously reported in healthy rodents. However, the skeletal muscle CO concentrations in dolphins from this study were much lower than those of deep-diving elephant seals. These results highlight the diversity and pattern of CO found in different tissues from bottlenose dolphins and continues to show that the heme oxygenase/carbon monoxide pathway appears to be critical for air-breathing divers.

physiology↗

bioRxiv2022

Assessing Functional Androgen Receptor Pathway Activity in Response to Radiotherapy Using hK2-targeted PET Imaging

External beam radiotherapy (EBRT) remains a common treatment for all stages of PCa, but DNA damage induced by EBRT upregulates androgen receptor (AR) pathway activity to promote therapeutic resistance. [89Zr]11B6-PET is a novel modality targeting prostate-specific protein human kallikrein 2 (hK2), which is a surrogate biomarker for AR activity. Here, we studied if [89Zr]11B6-PET can accurately assess EBRT-induced AR activity. PCa mouse models received EBRT (2-50 Gy) and treatment response was monitored by [89Zr]11B6-PET/CT. Radiotracer uptake and expression of AR and AR target genes was quantified in resected tissue. EBRT increased AR pathway activity in LNCaP-AR tumors. EBRT increased prostate-specific [89Zr]11B6 uptake and hK2 levels in PCa-bearing mice (Hi-Myc x Pb_KLK2) with no significant changes in uptake in healthy (Pb_KLK2) mice. Thus, [89Zr]11B6-PET specifically detects activation of AR pathway activity after EBRT in PCa. Further clinical evaluation of hK2-PET for monitoring EBRT is warranted.

cancer biology↗