Abstract 4484: BTP-114: An albumin binding cisplatin prodrug with improved and sustained tumor growth inhibition

Abstract

Platinum drugs have proven to be effective in treating cancer, for example >90% of men with testicular cancer are cured with a platinum therapeutic. Platinum drugs are also widely used for the adjuvant treatment of common cancers such as those of the lung, colon and ovary. However for the majority of tumor types the clinical response rates for platinum therapies are low, for example the 1 year survival rate for lung cancer patients treated with platinum therapeutics is ∼30%. The key limitations of the existing platinum therapies are the dose limiting toxicities that restrict dose and/or duration of therapy and the absence of personalization that targets the drugs to the patients most likely to benefit. To address these issues we have designed a novel prodrug of cisplatin, BTP-114. On infusion into the blood a maleimide group on BTP-114 covalently attaches to serum albumin. This prolongs the circulation of BTP-114 in plasma and alters the biodistribution of the compound. Importantly the dose of platinum can be increased and the amount of platinum that accumulated in xenograft tumor tissue and the amount of platinum bound to tumor DNA are both increased relative to cisplatin. An elevation of DNA damage in tumor cells in vivo is observed with BTP-114. Together the properties of BTP-114 result in pronounced and sustained tumor growth inhibition compared to cisplatin. In parallel to the discovery of BTP-114 we have explored potential biomarkers to predict which tumors are most likely to respond. These data will be presented towards developing BTP-114 as a personalized platinum medicine for cancer patients. BM and RA contributed equally to this work. Citation Format: Benoit Moreau, Rossitza Alargova, Adam Brockman, Kerry Whalen, Jamie Quinn, Kristan Meetze, Patrick Bazinet, Michelle DuPont, Beata Krawiec, Kristina Kriksciukaite, Charles Lemelin, Patrick LimSoo, Haley Oller, Mike Ramstack, Danielle Rockwood, Rajesh Shinde, Sukhjeet Singh, Brian White, Tsun AuYeung, Craig Dunbar, Mark Bilodeau, Richard Wooster. BTP-114: An albumin binding cisplatin prodrug with improved and sustained tumor growth inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4484. doi:10.1158/1538-7445.AM2015-4484

A Drug of Such Damned Nature.1 Challenges and Opportunities in Translational Platinum Drug Research

“…Molecules such as Evans Blue are avid albumin binders and used on that basis to assess BBB integrity (or similarly tethered to Pt­(IV)) . Along with prolonged pharmacokinetics, 2 may also be anticipated to benefit from the leaky tumor effect that can allow for high macromolecule accumulation in tumors…”

“…Schematic of a likely mechanism of action of a compound similar to 2 , based on disclosed description of mechanism . A Pt­(IV) complex containing cisplatin in the equatorial plane, with a pendent maleimide on an axial ligand (left), conjugates with Cys34 of human albumin in the bloodstream.…”

“…114 2 has been disclosed to be a prodrug of cisplatin with a pendent maleimide group, which covalently binds to serum albumin, providing an extended plasma half-life. 117 Maleimides react with thiols, and human albumin contains a single thiol at residue 34 9 that has been demonstrated to be accessible to maleimide conjugation. 118 On the basis of the disclosure information, it seems likely that 2 is a Pt(IV) complex with axial ligands containing functionalized maleimide groups.…”

Are Pt(IV) Prodrugs That Release Combretastatin A4 True Multi-action Prodrugs?

“…While direct covalent binding of cisplatin to albumin serves to inactivate the drug by reducing its bioavailability, the efficacy of Pt­(IV) prodrugs can be enhanced by deliberately targeting (covalently , or non-covalently) albumin in vivo, using it to deliver the cytotoxic agent to the tumor. One such compound, BTP-114, is in clinical trials …”

“…One such compound, BTP-114, is in clinical trials. 36 The binding of cisplatin, cisPt(CA4)OH, cisPt(CA4)(PhB), and cisPt(CA4-glu)(PhB), which were tested in vivo, to fetal calf serum (FCS) proteins (10 v/v %) in Dulbecco's modified Eagle's medium (DMEM) was evaluated over 24 h in an ethanol precipitation assay. The respective complexes were added to the medium, and aliquots were collected at different time points.…”