Heterobivalent ligands target cell-surface receptor combinations in vivo

Abstract

A challenge in tumor targeting is to deliver payloads to cancers while sparing normal tissues. A limited number of antibodies appear to meet this challenge as therapeutics themselves or as drug-antibody conjugates. However, antibodies suffer from their large size, which can lead to unfavorable pharmacokinetics for some therapeutic payloads, and that they are targeted against only a single epitope, which can reduce their selectivity and specificity. Here, we propose an alternative targeting approach based on patterns of cell surface proteins to rationally develop small, synthetic heteromultivalent ligands (htMVLs) that target multiple receptors simultaneously. To gain insight into the multivalent ligand strategy in vivo, we have generated synthetic htMVLs that contain melanocortin (MSH) and cholecystokinin (CCK) pharmacophores that are connected via a fluorescent labeled, rationally designed synthetic linker. These ligands were tested in an experimental animal model containing tumors that expressed only one (control) or both (target) MSH and CCK receptors. After systemic injection of the htMVL in tumor-bearing mice, label was highly retained in tumors that expressed both, compared with one, target receptors. Selectivity was quantified by using ex vivo measurement of Europium-labeled htMVL, which had up to 12-fold higher specificity for dual compared with single receptor expressing cells. This proof-of-principle study provides in vivo evidence that small, rationally designed bivalent htMVLs can be used to selectively target cells that express both, compared with single complimentary cell surface targets. These data open the possibility that specific combinations of targets on tumors can be identified and selectively targeted using htMVLs.receptor targeting | multivalency | cross-linking | gene expression profiling

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

“…Replacement of the fluorescent label with a chemotherapeutic can result in a highly selective drug targeting strategy [248-254]. This heterobivalent ligand targeting strategy has been validated both in vitro and in vivo [248-253]. In 2012, Xu et al .…”

Synthesis and bioactivity of MSH4 oligomers prepared by an A2+ B2 strategy

“…39 The B 2 co-monomer 4 incorporates the semi-rigid hexapeptide (Pro-Gly) 3 , which has proven useful in previous multivalent constructs involving melanocortin ligands. 12,40,41 …”

Principles in the design of ligand-targeted cancer therapeutics and imaging agents

“…Although PSMA is expressed at lower levels, many prostate cancers, including the LNCaP (PSMA + ) prostate cancer cell line, express in excess of one million receptors per cell 55 . Other receptors that may be present in sufficient quantities on cancer cells to be useful for targeted drug delivery include somatostatin receptor 2 (SSTR2) [56][57][58] , cholecystokinin type B receptor (CCKBR) [59][60][61] , bombesin receptor [62][63][64] , and sigma non-opioid intracellular receptor 1 (SIGMAR1) and SIGMAR2 (REFS. [65][66][67][68][69].…”