Delivery Of Cytotoxic Drugs Research Articles

P2798Final 5-year outcomes of the TRIAS High Risk of Restenosis; a multi-centre, randomized trial comparing endothelial progenitor cell capturing stent with drug-eluting stents

Abstract Background One of the major long-term disadvantages of percutaneous coronary intervention (PCI) remains in-stent restenosis and need for repeat revascularisation. The polymer-regulated delivery of cytotoxic or cytostatic drugs, on drug-eluting stents (DES), impede the natural healing response of the damaged vessel wall. In animals, endothelial progenitor cells (EPCs) beneficially influence the repair of the coronary vessel wall after damage by stent placement. It is hypothesized that after immobilisation the EPCs differentiate into a functional endothelial layer and that this layer will prevent neointimal proliferation and thrombus formation. Anti-CD34+ antibodies are able to capture the EPCs. The Genous stent consist of a bare-metal stent with anti-CD34+ antibody coating. Purpose Demonstrating long-term performance of Genous EPC capturing stent (ECS) relative to DES regarding target lesion failure (TLF); the composite of cardiac death, myocardial infarction (MI) and any target lesion revascularisation (TLR) within 5 years. Methods We undertook an international, clinical trial in 26 centres planning to randomise 1300 patients with stable coronary artery disease and with a high risk of restenosis between treatment with either ECS or DES. After a routine review with 50% of the patients enrolled, early cessation of the trial was recommended by the data and safety monitoring board when TLF in the ECS population was substantially higher and treatment of new patients with an ECS would be unreasonable. The trial was terminated for safety reasons. Results A total of 622 were randomly assigned to receive either Genous ECS (304 patients, 367 lesions) or DES (318 patients, 388 lesions). Five year follow-up data was obtained in 95.5% of patients. TLF occurred in 29.1% of the ECS-treated patients and in 16.0% of the DES-treated patients (p<0.001) (Figure 1). This difference was driven by higher rates of TLR (22.9% vs. 10.7%, p<0.001), but not by cardiac death (6.5% vs. 4.5%, p=0.268), or MI (5.8% vs. 3.6%, p=0.175). Definite or probable stent thrombosis was seen in 8 ECS-treated patients (2.7%) and in 3 DES-treated patients (1%), p=0.11. Figure 1. KM curves of TLF at 5year fu. Conclusion The Genous ECS is not sufficiently strong to compete with DES in terms of restenosis prevention in patients/lesions with a high risk of restenosis. If the addition of a EPCs capturing layer on a DES, like the COMBO stent, provides a lower risk of restenosis compared to DES will be tested in the ongoing SORT-OUT X trial. Acknowledgement/Funding OrbusNeich

Fabrication and design of dendrimers for cancer chemotherapy

Since the discovery of dendrimers in 1978, it has received serious attention as a drug carrier polymer most especially in cancer chemotherapeutics where precision and targeted delivery of drug to tumor cells is most desirable. Dendrimers are mostly synthetic, hyper-branched, tree-like globular, nano-sized polymers with excellent physicochemical properties that can be utilized in the formulation, design and delivery of drugs, vaccine and genes to specific receptors in the body. This review focused on the synthesis, types and applications of dendrimers in the delivery of cytotoxic drugs. The review shows that in the last decade, dendrimers have proved to be promising nanocarriers for various drugs including anti-inflammatory, antimicrobial, and anticancer drugs. The application of dendrimers as scaffolds of prodrugs is particularly interesting. Dendrimers are relatively more stable compared with other nano drug carriers and are suitable in formulating drugs for different routes of administration. As more and newer dendrimers are introduced into the market, they will have increasing role in therapeutic delivery of drugs, vaccines and gene.Keywords: Dendrimers, Targeted drug delivery and Cancer chemotherapy

An ultrasound-controllable release system based on waterborne polyurethane/chitosan membrane for implantable enhanced anticancer therapy.

Anti-relapse therapy after surgery plays a critical role in cancer therapy. New strategies maximizing the delivery of drugs to tumor cells while reducing toxic side effects on normal tissues and organs are still urgently required. In order to solve the problems of the poor delivery and inadequate distribution of cytotoxic chemotherapeutic drugs in the clinical application, an ultrasound-controllable and implantable release-system that utilized waterborne polyurethane (WPU) and chitosan (CS) composite membrane as drug carrier with wide flexible loading capacity for doxorubicin (DOX) was described in present work. Benefiting from the hydrophilic segment in WPU and bioactivity of amino groups on side chains of CS, the resulting composite films exhibited fine biodegradability, favorable cytocompatibility and excellent blood compatibility. The in vitro release studies illustrated that the drug-loading membranes displayed a well sustained release effect manifested in slow release, stability and no sudden release, and the DOX was able to release in an ultrasound-controlled manner. Cellular uptake assay and CCK 8 assay showed that the DOX can be released efficiently from the drug-loading matrix and taken up by tumor cells. As a means of adjuvant local treatment, this work provided a facile approach to the design of ultrasound-regulated membrane matrix that is highly beneficial not only due to the higher and long-term therapeutic efficiency, and improvement of utilization efficiency of chemotherapeutic drugs but also the low toxicity to normal cells.

Abstract LB-002: SQ3370 enhances the safety of chemotherapeutics via local activation therapy

Abstract With systemic chemotherapy, only 1-2% of the administered dose actually reaches a localized tumor, while the remaining leads to adverse off-target toxicities, including immunosuppression. Hence, there is a critical need to locally deliver cytotoxics directly to the tumor. Our patented approach (SQ3370) consists of: (1) SQL70 - a drug-activating biomaterial carrying no payload (2) SQP33 - a chemically-modified prodrug of doxorubicin (Dox) with attenuated activity. SQL70 is injected at the tumor site followed by SQP33 administered systemically. The prodrug first concentrates to the biomaterial at the tumor site due to their complementary chemical reactivities. The active drug is then spontaneously released over multiple days, providing sustained local delivery directly to the tumor region while reducing systemic side effects. Previously, we have shown that the greater safety of SQP33 allows it to be given at over 38 times the dose of standard Dox in SQL70-injected mice. Pharmacokinetic and biodistribution studies in SQ3370-treated rodents and dogs show that SQP33 disappears from plasma within the first hour of administration, likely due to the rapid concentration to SQL70. Without SQL70, SQP33 shows minimal spontaneous conversion to activated Dox. These studies also indicate that a single injection of SQL70 can activate multiple doses of SQP33, maximizing the local therapeutic index. Recent studies demonstrate that SQ3370 treatment enhances therapeutic response and survival in tumor-bearing mice: In a syngeneic MC38 colorectal cancer model, SQ3370 slowed tumor progression in 8/10 mice, showing improved efficacy compared to standard Dox or anti-PD-1 therapy. In mice bearing dual tumors, with one tumor site injected locally with SQL70, we observed that SQP33 can induce a response in both primary and secondary tumors, suggestive of an anti-tumor immune activation effect. Furthermore, we found that SQ3370 synergizes with anti-PD-1, expanding potential treatment options in the clinic and highlighting the advantages of immune-sparing cytotoxic therapy. Collectively, our results demonstrate that SQ3370 enables delivery of cytotoxic drugs to a target site while limiting exposure in off-target tissues in small and large animals, leading to improvements in both safety and efficacy. Citation Format: Nathan A. Yee, Sangeetha Srinivasan, Maksim Royzen, Jose M. Mejia Oneto. SQ3370 enhances the safety of chemotherapeutics via local activation therapy [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 LB-002.

Abstract 237: Preclinical evaluation of anti-HER2 Antibody Targeted Amanitin Conjugates (ATACs) on HER2low breast cancer with chromosome 17p deletion

Abstract Background: Triple negative breast cancer (TNBC) is the most difficult to treat subtype of breast cancer with limited therapeutic options. At least 50% of TNBC patients have low epidermal growth factor receptor 2 (HER2; ERBB2) expression with the majority harboring hemizygous loss of POLR2A/chromosome 17p. For these patients the treatment with antibody-targeted amanitin conjugates (ATACs) targeting HER2 is a new promising approach. ATACs comprise a new class of antibody-drug conjugates (ADCs) using amanitin as toxic payload and are able to kill antigen low expressing cells. Amanitin binds to the eukaryotic RNA polymerase II and thereby efficiently inhibits the cellular transcription process. In the current study, in vitro and in vivo data of ATACs targeting human HER2low as well as tolerability studies are presented. HER2low TNBC is considered an interesting target for amanitin-based ADCs. Material and methods: Different HER2 expressing cell lines were treated with anti-HER2 ATACs. Cysteine reactive amanitin-linkers were conjugated site-specifically to engineered cysteine residues of an anti-HER2 antibody yielding ATACs with a DAR of 2.0. Quantitative determination of cell viability was analyzed by BrdU ELISA assay. Subcutaneous mouse xenograft models with HER2-positive cell lines were performed with single-dose treatments. In addition, ATAC efficacy was tested in HER2low heterogeneous TNBC patient derived xenograft (PDX) models with and without POLR2A deletion. Tolerability of ATACs was assessed in mice and non-human primates (NHP). Results: Anti-HER2 ATACs showed in vitro cytotoxicity on HER2+ high and low cell lines in low nanomolar to picomolar range. In mouse xenograft models, the anti-HER2 ATACs caused dose-dependent tumor regression independent of Her2 expression level. In HER2low heterogeneous TNBC PDX models anti-HER2 ATACs caused dose-dependent tumor regression. The efficacy of anti-Her2 ATACs was more pronounced in PDX models with hemizygous loss of TP53 and POLR2A reflecting a 17p deletion. Safety profiling of an optimized anti-Her2 ATAC in cynomolgus monkeys revealed a good tolerability indicating a good therapeutic window for 17p deleted TNBC. Conclusions: Targeted cytotoxic drug delivery to HER2 positive cell lines was achieved by using anti-HER2 ATACs. The mode of action of the payload amanitin led to an efficient anti-tumor potential in vitro and in vivo with good tolerability in NHP studies. TNBC PDX models with HER2low expression were sensitive to ATAC treatment. Loss of POLR2A/chromosome 17p increased susceptibility to anti-HER2 ATAC making 17p del TNBC a suitable indication for optimized anti Her2 ATACs. Citation Format: Christian Breunig, Anikó Pálfi, Michael Kulke, Christian Lutz, Christoph Müller, Torsten Hechler, Andreas Pahl. Preclinical evaluation of anti-HER2 Antibody Targeted Amanitin Conjugates (ATACs) on HER2low breast cancer with chromosome 17p deletion [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 237.

A quantitative in silico platform for simulating cytotoxic and nanoparticle drug delivery to solid tumours.

The role of tumour-host mechano-biology and the mechanisms involved in the delivery of anti-cancer drugs have been extensively studied using in vitro and in vivo models. A complementary approach is offered by in silico models, which can also potentially identify the main factors affecting the transport of tumour-targeting molecules. Here, we present a generalized three-dimensional in silico modelling framework of dynamic solid tumour growth, angiogenesis and drug delivery. Crucially, the model allows for drug properties-such as size and binding affinity-to be explicitly defined, hence facilitating investigation into the interaction between the changing tumour-host microenvironment and cytotoxic and nanoparticle drugs. We use the model to qualitatively recapitulate experimental evidence of delivery efficacy of cytotoxic and nanoparticle drugs on matrix density (and hence porosity). Furthermore, we predict a highly heterogeneous distribution of nanoparticles after delivery; that nanoparticles require a high porosity extracellular matrix to cause tumour regression; and that post-injection transvascular fluid velocity depends on matrix porosity, and implicitly on the size of the drug used to treat the tumour. These results highlight the utility of predictive in silico modelling in better understanding the factors governing efficient cytotoxic and nanoparticle drug delivery.

Soft tissue sarcoma in dogs: A treatment review and a novel approach using electrochemotherapy in a case series

Canine soft tissue sarcomas (STSs) are locally invasive mesenchymal neoplasms. Electrochemotherapy (ECT) is an antitumour local ablative treatment that uses electric pulses to enhance the intracellular delivery of cytotoxic drugs. The aim of this retrospective study was to review the current treatment for STSs and to evaluate the efficacy and safety of ECT with bleomycin in canine STSs. Fifty-two dogs with 54 STSs were included. Three groups were arranged: (a) ECT alone, (b) intra-operative ECT and (c) adjuvant ECT. Signalment, tumour size, location, histological grade and margins and ECT parameters were collected. Recurrence rate (RR) and disease-free interval (DFI) were calculated. Treatment toxicity was assessed using a 6-point scale. STSs were mostly located on limbs (77.8%). Median tumour size was 4.3 cm (range 0.4-17.0 cm). Most STSs were grade I (47.7%) and II (50.0%), and histological margins were incomplete in 94.5% of cases. Two complete remissions, one partial remission and one stable disease were recorded in group 1. Group 2 and 3 were similar for tumour location, size and grade, histological margins, treatment toxicity, pulse frequency and voltage. Moreover, RR and DFI were similar between group 2 and 3 (23% and 25%, 81.5 and 243 days, respectively). Local toxicity post ECT was mild (score ≤ 2) in 66.7% of cases. Higher toxicity score was associated with higher pulse voltage (1200 vs 1000 V/cm) (P = 0.0473). ECT coupled with bleomycin resulted safe and efficient in tumour local control and should be considered as an option for treatment of canine STSs.

Antibody-drug therapeutic conjugates: Potential of antibody-siRNAs in cancer therapy.

Codelivery is a promising strategy of targeted delivery of cytotoxic drugs for eradicating tumor cells. This rapidly growing method of drug delivery uses a conjugate containing drug linked to a smart carrier. Both two parts usually have therapeutic properties on the tumor cells. Monoclonal antibodies and their derivatives, such as Fab, scFv, and bsAb due to targeting high potent have now been attractive candidates as drug targeting carrier systems. The success of some therapeutic agents like small interfering RNA (siRNA), a small noncoding RNAs, with having problems such as enzymatic degradation and rapid renal filtration need to an appropriate carrier. Therefore, the aim of this study is to review the recent enhancements in development of antibody drug conjugates (ADCs), especially antibody-siRNA conjugates (SRCs), its characterizations and mechanisms in innovative cancer therapy approaches.

Encapsulation of Emulsion Droplets with Metal Shells for Subsequent Remote, Triggered Release.

A two-step method to encapsulate an oil core with an impermeable shell has been developed. A thin metallic shell is deposited on the surface of emulsion droplets stabilized by metal nanoparticles. This thin shell is shown to prevent diffusion of the oil from within the core of the metal-shell microcapsules when placed in a continuous phase that fully dissolves the oil. The stabilizing nanoparticles are sterically stabilized by poly(vinyl pyrrolidone) chains and are here used as a catalyst/nucleation site at the oil-water interface to grow a secondary metal shell on the emulsion droplets via an electroless deposition process. This method provides the simplest scalable route yet to synthesize impermeable microcapsules with the added benefit that the final structure allows for drastically improving the overall volume of the encapsulated core to, in this case, >99% of the total volume. This method also allows for very good control over the microcapsule properties, and here we demonstrate our ability to tailor the final microcapsule density, capsule diameter, and secondary metal film thickness. Importantly, we also demonstrate that such impermeable microcapsule metal shells can be remotely fractured using ultrasound-based devices that are commensurate with technologies currently used in medical applications, which demonstrate the possibility to adapt these microcapsules for the delivery of cytotoxic drugs.

Correction: In-silico dynamic analysis of cytotoxic drug administration to solid tumours: Effect of binding affinity and vessel permeability.

[This corrects the article DOI: 10.1371/journal.pcbi.1006460.].

Phage Display Libraries: From Binders to Targeted Drug Delivery and Human Therapeutics.

The application of repertoire selection technologies for the study and characterization of tumor heterogeneity is an area of great interest in the field of tumor biology and immunotherapy. Among the most promising approaches, phage display has been successfully used to select peptides and antibody fragments to a variety of different targets, including cancer cells, immune cells and cytokines. Peptides selected from phage display have been used to guide the delivery of lytic peptides, cytotoxic drugs, and nanoparticles to cancer cells with the aim to obtain more efficient and less toxic therapeutics. Additionally, antibodies developed through phage display are being used in the treatment of autoimmune diseases and in some cases metastatic cancers. This review provides a short description of how phage libraries are designed, and highlights the conversion of the isolated binders into human therapeutics and use in targeted therapies.

Cytotoxicity and pharmacokinetics study of nanostructured lipid carriers of mechlorethamine: Preparation, optimization and characterization

The present work was aimed to prepare, optimize and characterize nanostructured lipid carriers (NLCs) loaded with mechlorethamine for improvement in pharmacokinetics. Emulsification-ultrasonication method was used to formulate nanostructured lipid-based carriers. 3D-response surface methodology helped to explore the qualitative and quantitative relationship. Optimization was done by Box–Benhken design and response surface methodology using Stat–Ease design expert software. NLCs were spherical, non-aggregates with average size of 105.92 ± 1.04 nm and dispersity index 0.02; potential was around −30.1 ± 0.82 mV. The percentage entrapment efficiency and loading capacity of optimized NLCs was 91.7 ± 1.20% and 1.79 ± 0.11%, respectively. DSC revealed that the drug existed in amorphous form in NLCs. In-vitro cumulative percentage release study exhibited bi-phasic response. In case of NLCs; Tmax was achieved at 37.5 ± 0.56 min with a sharp increase in plasma level [Cmax value 0.62 ± 1.07 µg/ml]. The IC50 value was found to be 39.087 ± 0.13 and 21.39 ± 0.17 μM for pure mechlorethamine and NLCs, respectively. Nano-lipid carriers are prominent system for achieving delivery of cytotoxic nitrogen mustard drugs with improved therapeutic efficiency.

DM1 Loaded Ultrasmall Gold Nanoparticles Display Significant Efficacy and Improved Tolerability in Murine Models of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide with poor prognosis and limited options for treatment. Life expectancy after diagnosis is short; the currently available treatments are not well tolerated and have limited clinical benefit. There is a clear unmet clinical need for the development of new treatments. In this study, ultrasmall, 2 nm gold core nanoparticles (MidaCore) conjugated with the potent maytansine analogue DM1 (MTC-100038) were assessed as a systemic nanomedicine for the treatment of hepatocellular carcinoma. The platform improved overall tolerability of DM1, permitting ∼3-fold higher levels of drug to be administered compared to free drug. Dose for dose, MTC-100038 also facilitated delivery of ∼2.0-fold higher ( p = 0.039) levels of DM1 to the tumor compared to free DM1. MTC-100038 produced significant efficacy (tumor growth index ∼102%; p = <0.0001), in several murine xenograft models of HCC, and was superior to both free DM1 and the current standard of care, sorafenib. Furthermore, MTC-100038 displayed potent (nM) in vitro activity in various HCC primary patient derived cell lines and across various other different cancer cell types. These data demonstrate the potential of MidaCore nanoparticles to enhance tumor delivery of cytotoxic drugs and indicate MTC-100038 is worthy of further investigation as a potential treatment for HCC and other cancer types.

Targeted Delivery of Cytotoxic NAMPT Inhibitors Using Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) are a therapeutic modality that enables the targeted delivery of cytotoxic drugs to cancer cells. Identification of active payloads with unique mechanisms of action is a key aim of research efforts in the field. Herein, we report the development of inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) as a novel payload for ADC technology. NAMPT is a component of a salvage biosynthetic pathway for NAD, and inhibition of this enzyme results in disruption of primary cellular metabolism leading to cell death. Through derivatization of the prototypical NAMPT inhibitor FK-866, we identified potent analogues with chemical functionality that enables the synthesis of hydrophilic enzyme-cleavable drug linkers. The resulting ADCs displayed NAD depletion in both cell-based assays and tumor xenografts. Antitumor efficacy is demonstrated in five mouse xenograft models using ADCs directed to indication-specific antigens. In rat toxicology models, a nonbinding control ADC was tolerated at >10-fold the typical efficacious dose used in xenografts. Moderate, reversible hematologic effects were observed with ADCs in rats, but there was no evidence for the retinal and cardiac toxicities reported for small-molecule inhibitors. These findings introduce NAMPT inhibitors as active and well-tolerated payloads for ADCs with promise to improve the therapeutic window of NAMPT inhibition and enable application in clinical settings.

In-silico dynamic analysis of cytotoxic drug administration to solid tumours: Effect of binding affinity and vessel permeability.

The delivery of blood-borne therapeutic agents to solid tumours depends on a broad range of biophysical factors. We present a novel multiscale, multiphysics, in-silico modelling framework that encompasses dynamic tumour growth, angiogenesis and drug delivery, and use this model to simulate the intravenous delivery of cytotoxic drugs. The model accounts for chemo-, hapto- and mechanotactic vessel sprouting, extracellular matrix remodelling, mechano-sensitive vascular remodelling and collapse, intra- and extravascular drug transport, and tumour regression as an effect of a cytotoxic cancer drug. The modelling framework is flexible, allowing the drug properties to be specified, which provides realistic predictions of in-vivo vascular development and structure at different tumour stages. The model also enables the effects of neoadjuvant vascular normalisation to be implicitly tested by decreasing vessel wall pore size. We use the model to test the interplay between time of treatment, drug affinity rate and the size of the vessels’ endothelium pores on the delivery and subsequent tumour regression and vessel remodelling. Model predictions confirm that small-molecule drug delivery is dominated by diffusive transport and further predict that the time of treatment is important for low affinity but not high affinity cytotoxic drugs, the size of the vessel wall pores plays an important role in the effect of low affinity but not high affinity drugs, that high affinity cytotoxic drugs remodel the tumour vasculature providing a large window for the normalisation of the vascular architecture, and that the combination of large pores and high affinity enhances cytotoxic drug delivery efficiency. These results have implications for treatment planning and methods to enhance drug delivery, and highlight the importance of in-silico modelling in investigating the optimisation of cancer therapy on a personalised setting.

Current Applications of Gold Nanoparticles for Medical Imaging and as Treatment Agents for Managing Pancreatic Cancer

Pancreatic cancer is an extremely heterogeneous, malignant disease with a complicated tumor microenvironment and a dismal prognosis. Extensive stroma surrounding the cancer and the sequestering of chemotherapeutic agents play dominant roles in tumor growth and metastasis and in suppressing the delivery of cytotoxic drugs to tumor cells. Currently, nanoscience is in the forefront of developments aimed at devising novel techniques to treat tumors. Gold nanoparticles (GNPs) are often used as potential imaging and therapeutic agents for cancers, since they offer: (1) Passive targeting because of better permeation and retention effects, (2) photothermal effects caused by efficient light-to-heat conversion, and (3) the potential to use simple gold-thiol bioconjugation chemistry to conjugate desired molecules for targeted drug delivery. Together, these benefits can increase the therapeutic success of GNPs when used in combination with conventional treatment strategies, such as surgery, chemotherapy, or radiotherapy. In this review, we discuss current trends in GNP research in the field of pancreatic cancer theranostics.

Confocal Microscopy Reveals Cell Surface Receptor Aggregation Through Image Correlation Spectroscopy.

Confocal microscopy provides an accessible methodology to capture sub-cellular interactions critical for the characterization and further development of pre-clinical agents labeled with fluorescent probes. With recent advancements in antibody based cytotoxic drug delivery systems, understanding the alterations induced by these agents within the realm of receptor aggregation and internalization is of critical importance. This protocol leverages the well-established methodology of fluorescent immunocytochemistry and the open source FIJI distribution of ImageJ, with its inbuilt autocorrelation and image mathematical functions, to perform spatial image correlation spectroscopy (ICS). This protocol quantitates the fluorescent intensity of labeled receptors as a function of the beam area of the confocal microscope. This provides a quantitative measure of the state of target molecule aggregation on the cell surface. This methodology is focused on the characterization of static cells with potential to expand into temporal investigations of receptor aggregation. This protocol presents an accessible methodology to provide quantification of clustering events occurring at the cell surface, utilizing well established techniques and non-specialized imaging apparatus.

Magnetic Drug Targeting: A Novel Treatment for Intramedullary Spinal Cord Tumors

Most applications of nanotechnology in cancer have focused on systemic delivery of cytotoxic drugs. Systemic delivery relies on accumulation of nanoparticles in a target tissue through enhanced permeability of leaky vasculature and retention effect of poor lymphatic drainage to increase the therapeutic index. Systemic delivery is limited, however, by toxicity and difficulty crossing natural obstructions, like the blood spine barrier. Magnetic drug targeting (MDT) is a new technique to reach tumors of the central nervous system. Here, we describe a novel therapeutic approach for high-grade intramedullary spinal cord tumors using magnetic nanoparticles (MNP). Using biocompatible compounds to form a superparamagnetic carrier and magnetism as a physical stimulus, MNP-conjugated with doxorubicin were successfully localized to a xenografted tumor in a rat model. This study demonstrates proof-of-concept that MDT may provide a novel technique for effective, concentrated delivery of chemotherapeutic agents to intramedullary spinal cord tumors without the toxicity of systemic administration.

Nodular Regenerative Hyperplasia Induced by Trastuzumab Emtansine: Role of Emtansine?

Trastuzumab is a monoclonal antibody targeted against the Human Epidermal Growth Factor Receptor 2 (HER2) overexpressed in some breast cancer. This targeted therapy significantly improves the prognosis of these cancers. Recently an anti-HER2 antibodydrug conjugate was shaped in order to facilitate the targeted delivery of potent cytotoxic drug to cancer cells and to reduce resistance. This formulation, called trastuzumab emtansine (T-DM1), consists of the monoclonal antibody trastuzumab linked to a cytotoxic drug (a derivative of maytansine) via a chemical linker. Little is known about adverse reactions due to this new formulation. Herein we described the case of a woman suffering from a HER2-positive breast cancer, treated with trastuzumab for 30 months followed by T-DM1 monotherapy. After 12 months of T-DM1 treatment, a nodular regenerative hyperplasia confirmed by liver biopsy occurred. T-DM1 was stopped and medical imagery showed a resolution of the nodular regenerative hyperplasia. Unfortunately, hepatic metastasis progressed. Few cases of nodular regenerative hyperplasia induced by T-DM1 have been described so far. Further studies are needed to explore pathogenesis of nodular regenerative hyperplasia with this new antibody-drug conjugate treatment.

Abstract 952: MORAb-202, a folate receptor-alpha (FRA)-targeting antibody-eribulin drug conjugate (ADC), exhibits durable antitumor activity and payload-mediated bystander effects on the tumor microenvironment in triple-negative breast cancer

Abstract MORAb-202 is an antibody drug conjugate (ADC) consisting of farletuzumab (humanized anti-FRA mAb) and eribulin (as a payload, which are conjugated via a cathepsin B-cleavable linker. FRA is highly over-expressed in a large number of cancers including triple negative breast cancer (TNBC). Eribulin has been approved by Phase III study 305 for metastatic breast cancer patients who have previously received at least two chemotherapies. Moreover, exploratory subpopulation analysis from combined Phase III studies of 301 and 305 found that survival benefit by eribulin treatment was observed in HER2-negative and TNBC patients. Here we show the robust anti-tumor effects of MORAb-202 against patient-derived (PDX) TNBC xenograft models. MORAb-202 demonstrated target selectivity and favorable cytotoxic drug delivery to tumors across a series of in vitro and in vivo studies. First, we found that MORAb-202 showed highly specific cytotoxicity on FRA positive cell lines at various IC50 values (0.001~23nM) according to their FRA expression levels, with little off-target killing (IC50 &amp;gt;100nM) on FRA negative cells. Moreover, it demonstrated significant in vitro bystander cytotoxicity (&amp;gt;140-fold) in FRA negative cells co-cultured with FRA positive cells when compared to mono-cultured FRA negative cells. In vivo, a single administration of MORAb-202 (1, 2.5, 5mg/kg) in FRA positive xenograft models showed dose-dependent antitumor activity with no observable toxicity. Single administration of MORAb-202 (5mg/kg) on high FRA-expressing TNBC PDX models showed long-lasting complete tumor regression (4/8), while near-MTD dose of eribulin (3.2mg/kg) showed minimum relative tumor volume of 96%. One dose of MORAb-202 (5mg/kg) elicits partial responses even on stroma-rich, low FRA-expressing (3.7%) TNBC PDXs. Immunofluorescent staining of tumor specimens both from the pre-treatment and five days post-treatment mice revealed that MORAb-202 achieved target specific engagement to FRA-positive regions in the tumor. Notably, MORAb-202 treatment diminished the network structure of cancer associated fibroblasts. This phenomenon was confirmed in an independent FRA-positive xenograft model, collected days 3, 5, 7 and 9 post-treatment of MORAb-202. Finally, GLP toxicology studies in cynomolgus monkeys found no adverse effects on safety pharmacology endpoints (i.e., cardiovascular, CNS, respiratory function) in the intermittent repeated-dose (Q3W×2) of MORAb-202 nor changes in electrocardiography at doses up to 6 mg/kg. This dose is believed to be about five times higher than the projected effective dose based on PDX results and eribulin dose modelling. Cumulatively, these data strongly support MORAb-202 as a promising ADC drug candidate for FRA-positive cancers. Citation Format: Keiji Furuuchi, Xin Cheng, Katherine Rybinski, Tomoyuki Moriyama, James Fulmer, Chris Maddage, Andrew Milinichik, Keigo Tanaka, George Lai, Mary Lou Dula, Danielle Fernando, Luigi Grasso, Earl Albone, Toshimitsu Uenaka. MORAb-202, a folate receptor-alpha (FRA)-targeting antibody-eribulin drug conjugate (ADC), exhibits durable antitumor activity and payload-mediated bystander effects on the tumor microenvironment in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 952.