Biology subjects

Larson, S. M.

Publications and source records attributed to Larson, S. M..

3 recordsLinked to original sources

bioRxiv2020

PSA-targeted Alpha-, Beta- and Positron Emitting Immuno-Theranostics in Murine Prostate Cancer Models and Non-Human Primates

PurposeMost prostate cancer (PCa) patients treated with androgen receptor (AR)-signaling inhibitors develop therapeutic resistance due to restoration of AR-functionality. Thus, there is a critical need for novel treatment approaches. Here we investigate the theranostic potential of hu5A10, a humanized monoclonal antibody specifically targeting free prostate-specific antigen (KLK3). Experimental DesignLNCaP-AR xenografts (NSG mice) and KLK3_Hi-Myc transgenic mice were imaged with 89Zr- or treated with 90Y- or 225Ac-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma-counting, positron emission tomography (PET), autoradiography and microscopy. Therapeutic efficacy of [225Ac]hu5A10 and [90Y]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [89Zr]hu5A10 in non-human primates (NHP) were determined using PET. ResultsBiodistribution of radiolabeled hu5A10-constructs was comparable in different mouse models. Specific tumor uptake increased over time and correlated with PSA expression. Treatment with [90Y]/[225Ac]hu5A10 effectively reduced tumor burden and prolonged survival (p[≤]0.0054). Effects of [90Y]hu5A10 were more immediate than [225Ac]hu5A10 (TTN, p<0.0001) but less sustained (TTP, p<0.0001). Complete responses were observed in 7/18 [225Ac]hu5A10 and 1/9 mice [90Y]hu5A10. Pharmacokinetics of [89Zr]hu5A10 were consistent between NHPs and comparable to those in mice. [89Zr]hu5A10-PET visualized the NHP-prostate over the 2-week observation period. ConclusionsWe present a complete preclinical evaluation of radiolabeled hu5A10 in mouse PCa models and NHPs, and establish hu5A10 as a new theranostic agent that allows highly specific and effective downstream targeting of AR in PSA-expressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating PCa.

cancer biology↗

bioRxiv2020

A simple strategy to reduce the salivary gland and kidney uptake of PSMA targeting small molecule radiopharmaceuticals

The past five years have seen an increasing acceptance of peptide-based prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) agents for treatment of metastatic castration-resistant prostate cancer (mCRPC), with [177Lu]-DKFZ-PSMA-617 ([177Lu]-PSMA-617) emerging as the leading candidate. [177Lu]-PSMA-617 and other PSMA ligands have shown efficacy in reducing the tumor burden in mCRPC patients but irradiation to salivary gland and kidneys is a concern and dose limiting factor. Therefore, methods to reduce non-target organ toxicity are needed to safely treat patients and preserve their quality of life. Here, we report the effects of the addition of the cold PSMA ligand DKFZ-PSMA-11 (PSMA-11) on the uptake of [177Lu]-PSMA-617 in tumor, salivary glands and kidneys. Groups of athymic nude mice (n = 4) bearing PC3-PIP (PSMA+) tumor xenografts were administered with [177Lu]-PSMA-617 along with 0, 5, 100, 500, 1000 and 2000 pmoles of PSMA-11. Biodistribution studies 1 h post-administration revealed that [177Lu]-PSMA-617 uptake in PSMA-expressing PC3-PIP tumors was 21.71{+/-}6.13, 18.7{+/-}2.03, 26.44{+/-}2.94, 16.21{+/-}3.5, 13.52{+/-}3.68, and 12.03{+/-}1.96 %ID/g when 0, 5, 100, 500, 1000 and 2000 pmoles of PSMA-11 were added, respectively. Corresponding kidney uptake values were 123.14{+/-}52.52, 132.31{+/-}47.4, 84.29{+/-}78.25, 2.12{+/-}1.88, 1.16{+/-}0.36, 0.64{+/-}0.23 %ID/g, respectively. Corresponding salivary gland uptake values were 0.48{+/-}0.11, 0.45{+/-}0.15, 0.38{+/-}0.3, 0.08{+/-}0.03, 0.09{+/-}0.07, 0.05{+/-}0.02 % ID/g, respectively. Thus, uptake of PSMA TRT agents in salivary gland and kidney can be substantially reduced without impact on tumor uptake by adding cold PSMA-11. Our data provides proof-of-concept and we propose that similar strategy be pursued in future clinical trials to prevent xerostomia and renal toxicity arising from [177Lu]-PSMA-617.

pharmacology and toxicology↗

bioRxiv2019

Genetic signature of prostate cancer resistant to optimized hK2 targeted alpha-particle therapy

Hu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate specific enzyme human kallikrein 2 (hK2; KLK2). In multiple rodent models, Actinium-225 labeled hu11B6-IgG1 ([225Ac]hu11B6-IgG1) has shown promising treatment efficacy. In the current study we investigated options to enhance and optimize [225Ac]hu11B6 treatment. Firstly, we evaluated the possibility of exploiting IgG3, the immunoglobulin G (IgG) subclass with superior activation of complement and ability to mediate FC-gamma-receptor binding, for immunotherapeutically enhanced hK2 targeted alpha-radioimmunotherapy. Secondly, we compared the therapeutic efficacy of a single high activity vs. fractionated activity. Finally, we used RNA sequencing to analyze the genomic signatures of prostate cancer that progressed after targeted alpha therapy. [225Ac]hu11B6-IgG3 was a functionally enhanced alternative to [225Ac]hu11B6-IgG1 but offered no improvement of therapeutic efficacy. Progression free survival was slightly increased with a single high activity compared to fractionated activity. Tumor free animals succumbing after treatment revealed no evidence of treatment associated toxicity. In addition to upregulation of canonical aggressive prostate cancer genes, such as MMP7, ETV1, NTS and SCHLAP1, we also noted a significant decrease in both KLK3 (PSA) and FOLH1 (PSMA) but not in AR and KLK2, demonstrating efficacy of sequential [225Ac]hu11B6 in a mouse model.

cancer biology↗