Anti-cancer Antibody Trastuzumab-Melanotransferrin Conjugate (BT2111) for the Treatment of Metastatic HER2+ Breast Cancer Tumors in the Brain: an In-Vivo Study.

PURPOSE: The ability of human melanotransferrin (hMTf) to carry a therapeutic concentration of trastuzumab (BTA) in the brain after conjugation (in the form of trastuzumab-melanotransferrin conjugate, BT2111 conjugate) was investigated by measuring the reduction of the number and size of metastatic human HER2+ breast cancer tumors in a preclinical model of brain metastases of breast cancer. METHODS: Human metastatic brain seeking breast cancer cells were injected in NuNu mice (n = 6-12 per group) which then developed experimental brain metastases. Drug uptake was analyzed in relation to metastasis size and blood-tumor barrier permeability. To investigate in-vivo activity against brain metastases, equimolar doses of the conjugate, and relevant controls (hMTf and BTA) in separate groups were administered biweekly after intracardiac injection of the metastatic cancer cells. RESULTS: The trastuzumab-melanotransferrin conjugate (BT2111) reduced the number of preclinical human HER2+ breast cancer metastases in the brain by 68% compared to control groups. Tumors which remained after treatment were 46% smaller than the control groups. In contrast, BTA alone had no effect on reducing number of metastases, and was associated with only a minimal reduction in metastasis size. CONCLUSIONS: The results suggest the novel trastuzumab-melanotransferrin conjugate (BT2111) may have utility in treating brain metastasis and validate hMTf as a potential vector for antibody transport across the Blood Brain Barrier (BBB).

Antimicrobial properties of MX-2401, an expanded-spectrum lipopeptide active in the presence of lung surfactant.

MX-2401 is an expanded-spectrum lipopeptide antibiotic selective for Gram-positive bacteria that is a semisynthetic analog of the naturally occurring lipopeptide amphomycin. It was active against Enterococcus spp., including vancomycin-sensitive Enterococcus (VSE), vanA-, vanB-, and vanC-positive vancomycin-resistant Enterococcus (VRE), linezolid- and quinupristin-dalfopristin-resistant isolates (MIC(90) of 4 µg/ml), methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) (MIC(90) of 2 µg/ml), coagulase-negative staphylococci, including methicillin-sensitive Staphylococcus epidermidis (MSSE) and methicillin-resistant S. epidermidis (MRSE) (MIC(90) of 2 µg/ml), and Streptococcus spp. including viridans group streptococci, and penicillin-resistant, penicillin-sensitive, penicillin-intermediate and macrolide-resistant isolates of Streptococcus pneumoniae (MIC(90) of 2 µg/ml). MX-2401 demonstrated a dose-dependent postantibiotic effect varying from 1.5 to 2.4 h. Furthermore, MX-2401 was rapidly bactericidal at 4 times the MIC against S. aureus and Enterococcus faecalis, with more than 99.9% reduction in viable bacterial attained at 4 and 24 h, respectively. The MICs of MX-2401 against MRSA, MSSA, VSE, and VRE strains serially exposed for 15 passages to sub- to supra-MICs of MX-2401 remained within three dilutions of the original MIC. In contrast to that of the lipopeptide daptomycin, the antibacterial activity of MX-2401 was not affected in vitro by the presence of lung surfactant, and MX-2401 was active in vivo in the bronchial-alveolar pneumonia mouse model, in which daptomycin failed to show any activity. Moreover, the activity of MX-2401 was not as strongly dependent on the Ca(2+) concentration as is the activity of daptomycin. In conclusion, MX-2401 is a promising new-generation lipopeptide for the treatment of serious infections with Gram-positive bacteria, including hospital-acquired pneumonia.

Anti-inflammatory activity of cationic peptides: application to the treatment of acne vulgaris.

Cationic antimicrobial peptides exhibit potent antimicrobial activity against clinically relevant microorganisms including Propionibacterium acnes. Recent studies showed that, in addition to the antimicrobial activity, these peptides can exhibit an anti-inflammatory effect. These properties make cationic peptides attractive drug candidates for the treatment of acne vulgaris, a disease with both bacterial and inflammatory components. This review focuses on the anti-inflammatory activity of cationic antimicrobial peptides and its application for the treatment of acne vulgaris. The anti-inflammatory activity of cationic peptides in acne vulgaris can be explained by their ability to both bind proinflammatory bacterial factors (e.g. lipoteichoic acid), sequestering them from the site of inflammation, and to inhibit the secretion of proinflammatory cytokines (e.g. tumor necrosis factor-alpha, IL-1) by host cells. These anti-inflammatory effects combined with potent antimicrobial activity may translate into a novel therapeutic option for acne vulgaris.

Assay systems for measurement of anti-inflammatory activity.

It is widely accepted that cationic antimicrobial peptides possess potent microbicidal properties. Recent studies show that in addition to their antimicrobial action, these peptides can exhibit anti-inflammatory activity. The purpose of this chapter is to describe in vivo ear inflammation models that can be used for evaluating the anti-inflammatory activity of antimicrobial peptides. The models are based on different mechanisms of inflammation development and include irritant dermatitis (a model induced by a single application of 12-o-tetradecanoylphorbol acetate [TPA]) and allergic dermatitis, or delayed type hypersensitivity reaction (a model induced by repetitive application of oxazolone).

Ex vivo skin infection model.

Over the past decade, the emergence of bacterial strains resistant to conventional antibiotics has necessitated the discovery and development of new antimicrobial therapies. This chapter describes a skin infection model that is based on the use of excised skin derived from the domestic pig. The model conditions mimic the environment of human skin and efficiently support the growth of clinically relevant bacterial and fungal species, thus making it useful for evaluating the activity of antimicrobial peptides and other antibiotics as well as their respective formulations.

Novel antimicrobial lipopeptides with long in vivo half-lives.

The pharmacokinetic (PK) properties of novel lipopeptides (semi-synthetic amphomycin analogues) with potent activity against Gram-positive organisms were evaluated in mice and rats following single intravenous (i.v.) and oral administration. Following oral administration at 50mg/kg, plasma concentrations of amphomycin analogues were <0.3-0.9microg/mL, suggesting that oral availability was low. Following i.v. administration (5-10mg/kg), the majority of lipopeptides demonstrated a long half-life (5.2-8.0h in mice and 4.6-7.1h in rats), low clearance (0.005-0.016mL/min in mice and 0.050-0.084mL/min in rats) and a volume of distribution indicative of extracellular penetration (0.118-0.339L/kg in mice and 0.121-0.133L/kg in rats). The area under the plasma concentration-time curve extrapolated to infinity (AUC(0-infinity)) for a 10mg/kg i.v. dose was determined to be 601.7-791.7microgh/mL in mice and 511.1-850.2microgh/mL in rats. The long half-life and low clearance observed with these novel lipopeptides indicate that drug serum concentrations will remain above the target minimal inhibitory concentration (MIC) levels for significant periods of time. When combined with the potent efficacy of these agents against Gram-positive organisms, the results of the present study support further development of these lipopeptide analogues towards clinical evaluation.

Antimicrobial and antifungal activities of a novel cationic antimicrobial peptide, omiganan, in experimental skin colonisation models.

Omiganan pentahydrochloride is a novel, synthetic, cationic, antimicrobial peptide that is being developed for the prevention of catheter-related infections and the treatment of acne and rosacea. In this study, the efficacy of topical omiganan gel was evaluated in two skin colonisation models (ex vivo pig skin and in vivo guinea pig skin). When tested in the ex vivo pig skin colonisation model, omiganan 0.1-2% gels exhibited potent dose-dependent activity against gram-positive and gram-negative bacteria and yeasts; the maximum effect was observed at 1-2%. No significant difference was noted in activity toward meticillin-resistant and meticillin-sensitive Staphylococcus aureus, and drug activity was not affected by the inoculum size. The antimicrobial activity of omiganan 1% gel was rapid, with a 2.7 log(10)colony-forming unit (CFU)/site reduction in Staphylococcus epidermidis counts at 1 h post application and a 5.2 log(10)CFU/site reduction at 24 h. Additional studies in the guinea pig skin colonisation model confirmed the potent antimicrobial and antifungal activities of omiganan 1% gel. In conclusion, omiganan gels have been demonstrated to be rapidly bactericidal and fungicidal, with significant dose-dependent activity against a broad spectrum of infectious organisms. These results further confirm that the drug has the potential as a topical antimicrobial agent.