MMAE Delivery Using the Bicycle Toxin Conjugate BT5528

Abstract

The EphA2 receptor is found at high levels in tumors and low levels in normal tissue and high EphA2 expression in biopsies is a predictor of poor outcome in patients. Drug discovery groups have therefore sought to develop EphA2-based therapies using small molecule, peptide, and nanoparticle-based approaches (1-3). However, until now only EphA2-targeting antibody-drug conjugates (ADC) have entered clinical development. For example, MEDI-547 is an EphA2-targeting ADC that displayed encouraging antitumor activity in preclinical models and progressed to phase I clinical testing in man. Here we describe the development of BT5528, a bicyclic peptide ("Bicycle") conjugated to the auristatin derivative maleimidocaproyl-monomethyl auristatin E to generate the Bicycle toxin conjugate BT5528. The report compares and contrasts the Pharmacokinetics (PK) characteristics of antibody and Bicyclebased targeting systems and discusses how the PK and payload characteristics of different delivery systems impact the efficacytoxicity trade off which is key to the development of successful cancer therapies. We show that BT5528 gives rise to rapid update into tumors and fast renal elimination followed by persistent toxin

Drug Conjugates Based on a Monovalent Affibody Targeting Vector Can Efficiently Eradicate HER2 Positive Human Tumors in an Experimental Mouse Model

“…One interesting aspect of this and our previous study [13] is that the histology investigation did not reveal pathologic changes in the kidneys although the renal uptake was higher than the tumor uptake. There are similar observations with other engineered scaffold proteins, conjugated with microtubule polymerization inhibitory drugs, e.g., conjugates of PASylated DARPin with MMAF [30,32] and Bicycles conjugate with MMAE [12]. In these cases, a strong anti-tumor effect was observed without a pronounced effect on the kidneys, even though the renal uptake was higher that the tumor uptake.…”

“…Engineered scaffold proteins (ESPs) may be used as an alternative to mAbs for targeting tumor cells and have recently been investigated as carriers of cytotoxic drugs [12,13]. Affibody molecules constitute a class of ESPs, consisting of 58 amino acids arranged in an anti-parallel three-helix bundle [14].…”

Peptide–drug conjugate-based novel molecular drug delivery system in cancer

“…BT5528 can accumulate in tumor tissues with a very low plasma concentration, which increases the selectivity for killing tumor cells with low systematic toxicity. BT5528 has a short half-life, stable metabolism, low uptake in non-targeted tissues, and fast clearance to the bladder through the kidneys [25].…”

Progress and Future Directions with Peptide-Drug Conjugates for Targeted Cancer Therapy

“…BT5528 comprises a bicyclic peptide targeting the tumor antigen EphA2 linked to a cytotoxin (monomethyl auristatin E) via a tumor microenvironment cleavable linker [ 2 ]. A Phase I/II study of BT5528 in patients with recurrent advanced solid tumors expressing EphA2 (NCT04180371) started in Q4 2019 [ 65 , 66 ].…”