Aniruddha Sengupta

Abstract 4483: IO125, a novel Pt-based supramolecular therapeutic exhibits increased anti-cancer efficacy compared with oxaliplatin

Despite the widespread use of platinum chemotherapy, only few drugs have been approved in this class of molecules. Here, we describe a novel supramolecular chemistry-based platform technology to engineer more potent oxaliplatin analogues. In IO125, a unique platinum (II) is tethered to a cholesterol backbone via a monocarboxylato bond and an N→Pt coordination environment, releasing diaminocyclohexane (DACH)-platinum in a sustained pH-dependent manner. The molecule facilitates assembly into defined nanoscale supramolecular structures of uniform size distribution as measured using dynamic light scatter and electron microscopy. Such a supramolecular therapeutic demonstrates enhanced activity compared with oxaliplatin in 4T1 and MDA-MB-231 triple negative breast cancer lines. The uptake of IO125-based supramolecular therapeutic was 10-20 fold greater than free oxaliplatin in these cells. In addition, the nanoparticles exhibited significantly lower IC50 values in comparison to oxaliplatin in primary colorectal carcinoma lines generated from patient tumor sample. Nanostructures have been shown to exhibit superior pharmacokinetics profile and biodistribution to tumors due to an enhanced permeability and retention (EPR) effect. Based on these observations, we anticipate an IO125-based supramolecular therapeutic may emerge as a novel next-generation platinum-based potent anti-cancer agent. Citation Format: Monideepa Roy, Sk Samad Hossain, Arindam Sarkar, Aniruddha Sengupta, Nimish Gupta, Sajid Hussain, Aasif Ansari, Sanghamitra Mylavarapu, Shiladitya Sengupta. IO125, a novel Pt-based supramolecular therapeutic exhibits increased anti-cancer efficacy compared with oxaliplatin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4483. doi:10.1158/1538-7445.AM2014-4483

Abstract P5-03-03: Designing a novel platinum chemotherapeutic (IO-125) for treatment of breast cancer

Triple-negative breast cancer (TNBC) is an aggressive form of cancer occurring in 15-20% of breast cancer patients, with most patients relapsing on currently approved therapy. Recent studies have shown activity of platinum chemotherapy in this class of patients. IO-125 is a novel platinum (II) chemotherapeutic agent with an unique coordination environment. In this study, we investigated the anti-tumor activity of IO-125 in pre-clinical models of TNBC. The coordination environment in IO-125 facilitates supramolecular assembly and releases diaminocyclohexane (DACH)-platinum in a sustained pH-dependent manner. In vitro cell viability studies using an array of breast cancer cell lines shows IO-125 exerts increased potency compared to carboplatin or oxaliplatin. The maximum tolerated (platinum-equivalent) dose (MTD) of IO-125 in mice was 8-fold higher than the MTD (platinum-equivalent) dose of oxaliplatin. The biodistribution and pharmacokinetic profile of IO-125 in plasma and tumor revealed preferential tumor accumulation, significantly increased area-under-the-curve (AUC), a reduction in clearance (CL) and a longer terminal half-life (42 hours) in comparison to oxaliplatin (18 hours). In addition, DNA-Pt adduct formation in tumors was significantly higher for IO-125. When administered at their respective MTDs, IO-125 led to sustained regression of the tumor in a 4T1 syngeneic breast cancer model. Based on these observations, we conclude that IO-125 may emerge as a novel therapeutic against triple negative breast cancer. Citation Format: Sengupta A, Roy M, Sarkar A, Mylavarapu S, Modi S, Gupta N, B H, Hossain S, Ansari A, Pandey M, Yadav Y, Sengupta S. Designing a novel platinum chemotherapeutic (IO-125) for treatment of breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-03-03.

Abstract 2231: IO125 is a potent inducer of tumor immunogenicity

Combinatorial treatments with chemotherapeutics and immunotherapies are currently being investigated in several cancers. Chemotherapeutics can increase the immunogenicity of tumors besides modulating the immune system. Here we describe the development of a novel platinum-based therapeutic, IO-125, which assembles into stable nanoscale supramolecular structures. IO125 demonstrates enhanced activity compared with standard Pt drug across cancer lines. IO-125 preferentially targets tumors in vivo, and demonstrated improved efficacy in triple negative breast cancer (4T1), Lewis lung carcinoma (LLC) and melanoma (B16/F10) tumor models. Treatment with IO-125 elevates expression of immune-markers (including IGKC, PD-L1, PD-1, CD8A), which are associated with good prognosis. In addition, combinatorial treatment with IO-125 and antibody against immune checkpoint inhibitor(s) resulted in superior antitumor efficacy compared to treatment with antibody alone. This study shows that supramolecular therapeutics, especially IO125, can emerge as a novel approach to focally modulate the tumor immune contexture. Citation Format: Sanghamitra Mylavarapu, Shelly Kaushik, Yashpal Yadav, Monideepa Roy, Aniruddha Sengupta, Shiladitya Sengupta. IO125 is a potent inducer of tumor immunogenicity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2231.

IO-125: A novel supramolecular platinum chemotherapy for triple negative breast cancer.

153 Background: Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer patients, with a median survival of 13 months and limited treatment options. Recent studies have indicated clinical benefits in TNBC with platinum agents. We designed a novel platinum chemotherapeutic (IO-125), with platinum (II) tethered to cholesterol-based leaving group via a novel coordination environment, conferring properties unique from current platinum-based chemotherapies. In this study, we investigated the anti-tumor activity of IO-125 in pre-clinical models of TNBC. METHODS Cellular viability of IO-125 was assessed in TNBC cell lines using MTT assay, while Pt levels in cells, plasma and tumors were quantified using atomic absorption spectroscopy. Antitumor activity was assessed in MDA-MB-231 xenograft model. RESULTS We reportthat IO-125 shows enhanced cellular cytotoxicity and higher intracellular uptake as compared to oxaliplatin in TNBC lines. In addition to uptake by organic cation transporters known for transporting current platinum chemotherapies, IO-125 is also internalized via caveolin-mediated endocytic pathway, resulting in 10-20 fold greater uptake into cells as compared to oxaliplatin. Studies have implicated caveolin in TNBC progression and drug resistance, and harnessing this mechanism could confer enhanced activity. In animals bearing MDA-MB-231 xenografts, three cycles of IO-125 at well-tolerated doses (35 mg Pt/kg) resulted in significant tumor growth inhibition as compared to reported tumor inhibitions seen with existing platinum chemotherapies. Pharmacokinetic studies conducted in mice and rabbits indicate markedly improved profile of IO-125 as compared to oxaliplatin, showing a significantly higher area-under-the-curve (AUC), a substantial reduction in clearance and volume of distribution, with an enhanced half-life. CONCLUSIONS Collectively, our findings demonstrate that IO-125 exhibits superior pharmacokinetics profile and biodistribution to tumors, resulting in enhanced anti-tumor activity in a TNBC xenograft model. Based on these observations, we propose that IO-125 may emerge as a potentially effective platinum-based drug for TNBC patients.

Abstract 649: Supramolecular assembly of antibody-drug conjugates using CORDLink platform for targeted drug delivery

Antibody-drug conjugates (ADCs) have emerged as a promising class of cancer therapeutics for targeted drug delivery. However, the synthesis of novel linkers for generating stable ADCs remains a key goal in the development of effective ADCs. Here we describe a unique linker (CORDLink) platform technology based on coordination chemistry that maintains the integrity of the antibody without impacting binding to the target. Using an anti-HER2 monoclonal antibody and camptothecin, as examples of the targeting antibody and a highly cytotoxic payload respectively, we demonstrate that the linker enables the formation of a stable ADC via supramolecular coordinate bond. The robustness of our process and consistency was characterized through a variety of analytical tools, such as SE-HPLC, CEX-HPLC and HI-HPLC, while peptide mapping was done to elucidate the exact site of attachment. The ADCs were found to remain intact in media and serum using a fluorescence-based RP-HPLC method. The anti-HER2 antibody recognizes HER2 receptors on cancer cells inducing internalization of the conjugate. The ADC showed significant cytotoxicity in cells expressing HER2 receptor but not in HER2 negative cell lines with IC50s in the nM range. We have established robust characterization methods to validate and confirm the integrity of the prototype ADCs in vitro. Studies are underway to further evaluate these molecules in vivo. The CORDLink technology offers a highly versatile platform that can be leveraged to deliver a broad range of payloads to selected cells using different targeting molecules. Citation Format: Nimish Gupta, Johny Kancharla, Shelly Kaushik, Samad Hossain, Arindam Sarkar, Aniruddha Sengupta, Monideepa Roy, Shiladitya Sengupta. Supramolecular assembly of antibody-drug conjugates using CORDLink platform for targeted drug delivery. [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 649. doi:10.1158/1538-7445.AM2015-649