Discovery of a 9-mer Cationic Peptide (LTX-315) as a Potential First in Class Oncolytic Peptide

Abstract

Oncolytic immunotherapies represent a new promising strategy in the treatment of cancer. In our efforts to develop oncolytic peptides, we identified a series of chemically modified 9-mer cationic peptides that were highly effective against both drug-resistant and drug-sensitive cancer cells and with lower toxicity toward normal cells. Among these peptides, LTX-315 displayed superior anticancer activity and was selected as a lead candidate. This peptide showed relative high plasma protein binding abilities and a human plasma half-life of 160 min, resulting in formation of nontoxic metabolites. In addition, the lead candidate demonstrated relatively low ability to inhibit CYP450 enzymes. Collectively these data indicated that this peptide has potential to be developed as a new anticancer agent for intratumoral administration and is currently being evaluated in a phase I/IIa study.

The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade

“…Comparisons of Kaplan-Meier survival curves were performed using the log-rank Mantel-Cox test; NS, not significant LTX-315 overcomes anti-CTLA4 resistance T Yamazaki et al manner by inducing cell death endowed with immunogenic properties. [25][26][27][28][29][30][31][32][33][34][35] In this preclinical study, we found that LTX-315 can be active against sarcomas that poorly respond to CTLA4 blockade, and that the sequential combination of anti-CTLA4 mAb followed by LTX-315 is synergistic, either using systemic or local delivery of anti-CTLA4 mAb, with a mechanism involving CD122 receptors.…”

“…[19][20][21][22][23][24] The chemical modifications of bovine lactoferricin derivatives allowed for the development of a lead compound, LTX-315 with a shorter chemically modified peptide length and optimal (selective) anticancer properties. [25][26][27][28][29] By creating pores and disintegrating the cytoplasmic membranes, as well as targeting the mitochondria, LTX-315 promotes the release of damage-associated molecular patterns (DAMPs) associated with immunogenic cell death (ICD). 26,27,29 Transmission electron microscopy or morphometric analysis of chromatin-stained tumor cells revealed that LTX-315 failed to induce classical 'apoptosis' associated with apoptotic nuclear condensation and caspase-3-dependent cell death.…”

Anticancer activities of bovine and human lactoferricin-derived peptides

“…The design of this new peptide was originally derived from LFcinB and was the result of extensive structure-activity relationship studies (Haug et al 2016). In terms of hLF, the peptide derived from the first 11 residues (hLF11) has been extensively studied for its antimicrobial activity against several bacterial and fungal strains (Lupetti et al 2000, Nibbering et al 2001.…”

LTX-315: A First-In-Class Oncolytic Peptide that Reprograms the Tumor Microenvironment

“…The vast amount of SAR-data on lactoferricinderived, and also synthetic model peptides has facilitated the de novo design of 9-mer cationic peptides in which counterproductive residues have been deleted and the properties of residues identified as important for anticancer activity have been optimized, thereby resulting in a series of 9-mers composed of five cationic residues, two or three tryptophan residues and one or two bulky and lipophilic unnatural residues [29]. These peptides were found to be highly effective against both drug-resistant and drug-sensitive cancer cells, and displayed a lower activity toward normal cells.…”

“…LTX-315 has been shown to be highly active against a wide variety of both murine and human cancer cell lines in vitro [29][30][31][32][33][34].…”