Therapeutic Efficacy of 177Lu-Labeled A20FMDV2 Peptides Targeting ανβ6

Abstract

Integrin ανβ6 promotes migration and invasion of cancer cells, and its overexpression often correlates with poor survival. Therefore, targeting ανβ6 with radioactive peptides would be beneficial for cancer imaging and therapy. Previous studies have successfully developed radiotracers based on the peptide A20FMDV2 that showed good binding specificity for ανβ6. However, one concern of these ανβ6 integrin-targeting probes is that their rapid blood clearance and low tumor uptake would preclude them from being used for therapeutic purposes. In this study, albumin binders were used to increase tumor uptake for therapeutic applications while the non-albumin peptide was evaluated as a potential positron emission tomography (PET) imaging agent. All peptides used the DOTA chelator for radiolabeling with either 68Ga for imaging or 177Lu for therapy. PET imaging with [68Ga]Ga-DOTA-(PEG28)2-A20FMDV2 revealed specific tumor uptake in ανβ6-positive tumors. Albumin-binding peptides EB-DOTA-(PEG28)2-A20FMDV2 and IBA-DOTA-(PEG28)2-A20FMDV2 were radiolabeled with 177Lu. Biodistribution studies in normal mice showed longer blood circulation times for the albumin binding peptides compared to the non-albumin peptide. Therapy studies in mice demonstrated that both 177Lu-labeled albumin binding peptides resulted in significant tumor growth inhibition. We believe these are the first studies to demonstrate the therapeutic efficacy of a radiolabeled peptide targeting an ανβ6-positive tumor.

Lipopolysaccharide and lipoteichoic acid regulate the PI3K/AKT pathway through osteopontin/integrin β3 to promote malignant progression of non-small cell lung cancer

“…It is also one of the indicators of increased lymph node or bone metastasis and decreased survival rate of patients in some cancers ( 18 ). Integrin β3 affects tumor cell initiation, survival, and stemness by regulating cytokines, thereby promoting carcinogenesis and tumor growth ( 19 ). In this study, we preliminarily analyzed the interaction between OPN and integrin β3 in the malignant bioactivity of lung cancer cells, which was similar to previous literature.…”

Synthesis and Systematic Study on the Effect of Different PEG Units on Stability of PEGylated, Integrin-αvβ6-Specific A20FMDV2 Analogues in Rat Serum and Human Plasma

“…The clinical potential of the PEGylated A20FMDV2 peptide incorporating larger PEG moieties (bis-PEG 28 ) has already been realized [ 47 ]. It has been reported in the past that the presence of either bis-PEG 28 , PEG 28 or PEG 7 within the A20FMDV2 peptide sequence has a positive effect on the peptide pharmacokinetics [ 24 , 37 , 38 , 39 , 40 , 41 , 42 , 46 ]. The current studies outlined here fulfil the gap in the knowledge where effects of other PEG moieties (PEG 1 -PEG 20 ) on A20FMDV2 stability have been investigated with the aim to identify the shortest ethylene glycol repeat that improves peptide stability.…”

“…In another study by the group, gallium-68 ([ 68 Ga])-DOTA-PEG 28 -A20FMDV2-PEG 28 and albumin binding, A20FMDV2-based peptides for the subsequent radiolabelling with lutetium-177 ( 177 Lu), namely Evans Blue azo dye (EB)-PEG 28 -A20FMDV2-PEG 28 and 4-( p -iodophenyl)butyric acid (IBA)-PEG 28 -A20FMDV2-PEG 28 , were tested for the αvβ6-specific cancer imaging and therapy [ 42 ]. It was shown that the enrichment of the probe with albumin binders increased the blood circulation time, but at the same time non-desired off-target radioactivity accumulation was also observed.…”

“…The inhibition of tumour growth in mice was also observed; however, toxicity, especially for the Evans Blue azo-dye-enriched analogue, proved to be problematic. Further optimisation of the probes is anticipated to address safety and reduce non-desired normal tissue uptake [ 42 ].…”

Peptide therapeutics in the management of metastatic cancers

“…These conjugates were further radiolabelled for aggravated and targeted tumor inhibition. 89 The α v β 5 integrin heightens angiogenesis and metastasis and has recently been targeted by an ACP named RGDechi15D. RGDechi15D was developed by modification of the RGDechi peptide which contains a cRGD motif fused to echistatin C-terminal domain.…”