Merrimack Pharmaceuticals (United States)

The first reported case of Malassezia furfur endocarditis in an adult patient is presented. The unique microbiological aspects of this organism, as well as the difficulties inherent in its antifungal susceptibility testing, are discussed.

Abstract Early attempts at using TNF superfamily members for anticancer therapies, TNF and FAS, led to serious systemic toxicities. However, the discovery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) introduced an agonist capable of killing tumor cells via apoptosis without the side effects observed with TNF and FAS agonists. First generation TRAIL agonists included a recombinant version of human TRAIL (dulanermin), as well as multiple DR4 and DR5 agonist antibodies. Despite some isolated responders, the initial clinical results were poor. The first-generation TRAIL agonists were limited by poor pharmacokinetics (the half-life for dulanermin was between 30 and 60 minutes) or by poor agonist activity and the need for Fc-mediated cross linking. Here we present the development and evaluation of two second generation TRAIL agonists, MM-201a and MM-201b. Both versions are composed of an IgG1 Fc fused to a single chain TRAIL trimer (Fc-scTRAIL). Mutations within the TRAIL domains, selected from a random mutagenesis library, were introduced to improve stability, expression, and DR5 binding. MM-201a has 5 mutations in each monomeric unit (R130G/N228S/I247V/Y213W/S215D) and MM-201b has 3 mutations in each monomer (R130G/N228S/I247V). In a panel of 27 colorectal carcinoma and sarcoma cell lines, both versions of MM-201 were observed to be significantly more active than all comparators, including the TRAIL cytokine and both DR4 and DR5 antibodies. MM-201a had a level of activity similar to ABBV-621, a single chain TRAIL fused to the N-terminus of an IgG1 Fc that is currently the subject of a Phase 1 trial. However, MM-201b was significantly more active than both MM-201a and ABBV-621, with up to 11-fold lower IC50 across a panel of 12 CRC cell lines. MM-201b treatment reduced cell viability to less than 20% in 10 out 12 colorectal cancer cell lines and in 8 of these cell lines, this was achieved at concentrations less than 1 nM. MM-201 also induced complete cell death at 1 nM or less in 3 of 8 synovial sarcoma and chondrosarcoma cell lines tested. For example, MM-201b reduced the viability of the SW-982 synovial sarcoma cell line to 17% at a dose of 1.5 pM, which is nearly twice the reduction in viability from the same dose of ABBV-621. We next evaluated both versions of MM-201 in multiple colorectal cancer and sarcoma patient-derived xenograft (PDX) models. In the Ewing’s sarcoma PDX model TM01617, MM-201b treatment resulted in 90% tumor growth inhibition. In the same model, treatment with 10 mg/kg docetaxel resulted in 73% growth inhibition; however, in combination with MM-201a, the same dose resulted in a 100% complete response rate. Similar results were observed in the SK-UT1 uterine sarcoma xenograft. Based on this evidence, we believe that MM-201b is best in class and, when combined with an appropriate patient selection strategy, has significant potential for the treatment of sarcomas and colorectal cancer in patients. Citation Format: Andrew J. Sawyer, Sara Ghassemifar, Christina Wong, Jennifer Richards, Stephanie Grabow, James Suchy, Alexander Koshkaryev, Maja Razlog, Eric Tam, Daryl C. Drummond. Engineering and preclinical activity of MM-201, a best-in-class TRAIL receptor agonist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2491.

Abstract This abstract was withdrawn by the authors. Citation Format: Ghassemifar S, Finn G, Zhang H, Richardson J, Kuesters G, Santillana S, Pipas M. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-19.

e16205Background: nal-IRI facilitates intratumoral drug deposition through enhanced permeability and retention, with pharmacokinetic and pharmacodynamic (PK/PD) analyses demonstrating an extended c...

Despite the advances in imaging, surgery and radiotherapy, the majority of patients with brainstem gliomas die within 2years after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which prevents total surgical resection and the presence of the blood-brain barrier (BBB), which reduces the distribution of systemically administered agents. The development of new therapeutic approaches which can circumvent the BBB is a potential path to improve outcomes for these children. Convection-enhanced delivery (CED) and intranasal delivery (IND) are strategies that permit direct drug delivery into the central nervous system and are an alternative to intravenous injection (IV). We treated rats bearing human brainstem tumor xenografts with nanoliposomal irinotecan (CPT-11) using CED, IND, and IV. A single treatment of CED irinotecan had a similar effect on overall survival as multiple treatments by IV route. IND CPT-11 showed significantly increased survival of animals with brainstem tumors, and demonstrated the promise of this non-invasive approach of drug delivery bypassing the BBB when combined with nanoliposomal chemotherapy. Our results indicated that using CED and IND of nanoliposomal therapy increase likelihood of practical therapeutic approach for the treatment of brainstem gliomas.

Purpose: To determine whether deposition characteristics of ferumoxytol (FMX) iron nanoparticles in tumors, identified by quantitative MRI, may predict tumor lesion response to nanoliposomal irinotecan (nal-IRI).Experimental Design: Eligible patients with previously treated solid tumors had FMX-MRI scans before and following (1, 24, and 72 hours) FMX injection. After MRI acquisition, R2* signal was used to calculate FMX levels in plasma, reference tissue, and tumor lesions by comparison with a phantom-based standard curve. Patients then received nal-IRI (70 mg/m2 free base strength) biweekly until progression. Two percutaneous core biopsies were collected from selected tumor lesions 72 hours after FMX or nal-IRI.Results: Iron particle levels were quantified by FMX-MRI in plasma, reference tissues, and tumor lesions in 13 of 15 eligible patients. On the basis of a mechanistic pharmacokinetic model, tissue permeability to FMX correlated with early FMX-MRI signals at 1 and 24 hours, while FMX tissue binding contributed at 72 hours. Higher FMX levels (ranked relative to median value of multiple evaluable lesions from 9 patients) were significantly associated with reduction in lesion size by RECIST v1.1 at early time points (P < 0.001 at 1 hour and P < 0.003 at 24 hours FMX-MRI, one-way ANOVA). No association was observed with post-FMX levels at 72 hours. Irinotecan drug levels in lesions correlated with patient's time on treatment (Spearman ρ = 0.7824; P = 0.0016).Conclusions: Correlation between FMX levels in tumor lesions and nal-IRI activity suggests that lesion permeability to FMX and subsequent tumor uptake may be a useful noninvasive and predictive biomarker for nal-IRI response in patients with solid tumors. Clin Cancer Res; 23(14); 3638-48. ©2017 AACR.

Abstract Aberrant signaling of the FGFR pathway has long been known to promote tumorigenesis and angiogenesis across multiple cancer indications. However, the development of an effective and well-tolerated FGFR targeted inhibitor has been hindered by the need to block the activation of multiple mitogenic receptors while avoiding significant toxicities associated with blocking endocrine FGF ligands. Here we disclose for the first time a novel FGFR targeted antibody, MM-161, designed to block ligand-dependent signaling driven by all four FGF receptors, specifically the IIIc-isoforms. MM-161 is well tolerated in mice and cynomolgus monkeys with no significant weight loss observed in either species. Efficacy studies demonstrated that MM-161 monotherapy leads to significant tumor growth inhibition or tumor regression of xenografts of human lung, renal and endometrial cancer amongst others. Importantly, MM-161 has a dual mechanism of action by inhibiting both proliferation and angiogenesis. We will present data illustrating that inhibition of multiple FGFRs is desirable to achieve tumor regression. Furthermore, we will show combination studies with relevant standard of care therapies in models of lung and renal cancer. Taken together, our preclinical data strongly supports the clinical evaluation of MM-161 in cancer patients. Citation Format: Tamara Dake, Greg Finn, Melissa Geddie, Neeraj Kohli, Maja Razlog, Lihui Xu, Violette Paragas, Haluk Yuzugullu, Sara Ghassemifar, Yasmin Hashambhoy-Ramsay, Charlotte McDonagh, Marco Muda, Birgit Schoeberl. MM-161, a first-in-class pan-FGFR antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 22. doi:10.1158/1538-7445.AM2017-22

Abstract The efficacy of the current class of PD-1/PD-L1 antagonists can be limited by the immunogenicity of the tumor microenvironment. Studies showed that some chemotherapeutic agents including taxanes and anthracyclines can increase immunogenicity, resulting in therapeutic synergy with immune checkpoint inhibitors. In particular, treatment with a taxane has been shown to increase the recruitment of CTLs and decrease immunosuppressive cells such as MDSCs and T-regs. Additionally, the immune-modulatory activity of paclitaxel has been shown to increase with prolonged exposure of the taxane at the tumor level, achieved through metronomic dosing. MM-310 is an Ephrin Receptor A2 (EphA2)-targeted antibody-directed nanotherapeutic (ADN) that encapsulates a docetaxel prodrug. Preclinically, MM-310 leads to prolonged exposure of docetaxel at the tumor level, while lowering systemic exposure to bioavailable docetaxel, and thus decreasing not only dose-limiting neutropenia but also the killing of circulating lymphocytes potentially critical to anti-PD1/PDL1 activity relative to free docetaxel. Taken together, we hypothesize that MM-310 can synergistically combine with anti-PD-1 therapy. In this study, we evaluated the potential combination of MM-310 and a murine anti-PD-1 Ab in the treatment of several syngeneic mouse tumor models. The tumor lines EMT-6, CT-26, and LLC were selected to provide a range of sensitivity to both docetaxel and anti-PD-1. In vivo activity studies and immune-phenotype studies were performed comparing MM-310+anti-PD-1 combination to the monotherapies. MM-310 administration was initiated two days prior to anti-PD-1 therapy and consisted of four weekly doses, while anti-PD-1 was dosed twice weekly for four weeks. The response to MM-310 or anti-PD-1 as monotherapies varied between the models. LLC was unresponsive to anti-PD-1 and poorly responsive to MM-310, CT-26 was poorly responsive to both anti-PD-1 and MM-310, while EMT-6 responded moderately to anti-PD-1 with tumor stasis and well to MM-310, achieving tumor regression. In all models, however, MM-310 given in combination with anti-PD-1 outperformed controls and both monotherapy arms in terms of growth inhibition and tumor regression rate. In the EMT-6 model, combination treatment resulted in durable complete regressions in 6/10 mice when compared to 2/10 and 0/10 for MM-310 and anti-PD-1 monotherapies respectively. In MM-310 and MM-310+anti-PD-1 groups, re-challenge of mice with the same tumor cells, at 10 weeks post treatment interruption, did not lead to tumor growth, suggesting that treatment with anti-PD1+MM-310 promotes the development of a memory response against the tumor antigen. In conclusion, the novel combination of MM-310, an EphA2-targeted docetaxel ADN with an anti-PD-1 antibody, is highly active in syngeneic tumor models, and represents a promising strategy for the treatment of cancer. Citation Format: Andrew J. Sawyer, Anne-Sophie Dugast, Lia Luus, Zhaohua Richard Huang, Suresh K. Tipparaju, Dmitri B. Kirpotin, Daryl C. Drummond, Walid S. Kamoun. Immunomodulatory effects of an EphA2-targeted docetaxel antibody-directed nanotherapeutic and synergistic combination with PD-1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4711. doi:10.1158/1538-7445.AM2017-4711

Abstract Targeted therapies have shown significant patient benefit in about 5-10% of solid tumors that are addicted to a single oncogene. Here, we explore the idea of ligand addiction as a driver of tumor growth. High ligand levels in tumors have been shown to be associated with impaired patient survival, but targeted therapies have not yet shown great benefit in unselected patient populations. Using a novel approach of applying Bagged Decision Trees (BDT) to high-dimensional signaling features derived from a computational model, we can predict ligand dependent proliferation across a set of 58 cell lines. This mechanistic, multi-pathway model that features receptor heterodimerization, was trained on seven cancer cell lines and can predict signaling across two independent cell lines by adjusting only the receptor expression levels for each cell line. Interestingly, for patient samples the predicted tumor growth response correlates with high growth factor expression in the tumor microenvironment, which argues for a co-evolution of both factors in vivo.SummaryPrediction of ligand-induced growth of cancer cell lines, which correlates with ligand-blocking antibody efficacy, could be significantly improved by learning from features of a mechanistic signaling model, and was applied to reveal a correlation between growth factor expression and predicted response in patient samples.