A Polymer-Based Antibody-Vinca Drug Conjugate Platform: Characterization and Preclinical Efficacy.

Antibody-drug conjugates (ADC) are an emerging drug class that uses antibodies to improve cytotoxic drug targeting for cancer treatment. ADCs in current clinical trials achieve a compromise between potency and physicochemical/pharmacokinetic properties by conjugating potent cytotoxins directly to an antibody at a 4:1 or less stoichiometric ratio. Herein, we report a novel, polyacetal polymer-based platform for creating ADC that use poly-1-hydroxymethylethylene hydroxymethyl-formal (PHF), also known as Fleximer. The high hydrophilicity and polyvalency properties of the Fleximer polymer can be used to produce ADC with high drug loading without compromising physicochemical and pharmacokinetic properties. Using trastuzumab and a vinca drug derivative to demonstrate the utility of this platform, a novel Fleximer-based ADC was prepared and characterized in vivo. The ADC prepared had a vinca-antibody ratio of 20:1. It exhibited a high antigen-binding affinity, an excellent pharmacokinetic profile and antigen-dependent efficacy, and tumor accumulation in multiple tumor xenograft models. Our findings illustrate the robust utility of the Fleximer platform as a highly differentiated alternative to the conjugation platforms used to create ADC currently in clinical development.

XMT-1001, a novel polymeric camptothecin pro-drug in clinical development for patients with advanced cancer.

An overview of XMT-1001 is provided in the context of other topoisomerase I inhibitors conjugated to polymers or encapsulated in liposomes. XMT-1001 is a novel polymeric pro-drug derivative of camptothecin (CPT) with a molecular weight of 70 kDa, in which CPT is chemically tethered to a hydrophilic, biodegradable polyacetal polymer, poly(1-hydroxymethylethylene hydroxymethylformal), also called PHF or Fleximer(R). XMT-1001 releases CPT via intermediates camptothecin-20-O-(N-succinimidoglycinate) (CPT-SI), and camptothecin-20-O-(N-succinamidoyl-glycinate) (CPT-SA) over an extended time period. XMT-1001 has an improved therapeutic window compared to CPT and irinotecan in human tumor xenograft models, providing a compelling rationale for clinical development. A unique feature of XMT-1001 is its dual phase release mechanism for CPT which may result in lower levels of CPT in the urine and less bladder toxicity, a serious dose limiting toxicity associated with CPT and CPT conjugated to other polymers. XMT-1001 is being evaluated in patients with advanced cancer in an ongoing Phase 1 trial.

Persistent silver disinfectant for the environmental control of pathogenic bacteria.

BACKGROUND: Contaminated surfaces can act as a reservoir for pathogenic microorganisms and potentially exacerbate the risk of infection. Surface disinfection and decontamination provide temporary amelioration against bacterial colonization. Disinfected surfaces eventually become contaminated, thus, mitigating the benefit of the initial disinfection. It is hypothesized that to improve on the current state of the art, a disinfectant should not only immediately disinfect a surface but also provide persistent antimicrobial action after the product has been applied. We describe here a silver-based disinfectant technology designed to provide long-lasting sanitization and disinfection to treated surfaces as evaluated on hard surfaces after repeated environmental insults. METHODS: A comparative evaluation of 6 disinfectant formulations for residual antimicrobial activity after water rinsing was performed. Log reduction of bacterial populations on disinfectant-treated substrates were measured after 30 minutes to 8 hours of exposure and compared with an untreated control. In a similar study, the residual antimicrobial activity of a silver disinfectant was evaluated against antibiotic- and biocide-resistant bacteria also after water rinsing. Further, residual antimicrobial activity of the silver disinfectant was measured after 5 cycles of rinsing, abrasion, and contamination against representative household and nosocomial pathogens (Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Enterobacter aerogenes, Enterococcus faecium, or Salmonella choleraesuis) after 10-minute exposure times. RESULTS: In the comparative assay, only the silver disinfectant and a persistent quaternary ammonium compound disinfectant demonstrated significant residual activity (> or =3.0 log(10) reduction to control) against S aureus whereas only the silver disinfectant demonstrated activity against Pseudomonas. No residual activity (< or = 0.5 log reduction to untreated control) was observed for the other disinfectant products. The silver-based disinfectant also showed significant and equivalent efficacy against antibiotic- and silver-resistant bacteria. In addition, the silver disinfectant was able to achieve significant residual activity in 10 minutes against all organisms tested after 1, 3, and 5 cycles of water rinse, abrasion, and microbial contamination. CONCLUSIONS: The findings show the ability of a new silver-based disinfectant to reduce bacterial populations that contact treated surfaces within minutes, highlight the potential to interrupt cross-contamination from environmental surfaces, and reduce the risk of infection within the home and health care settings.