Therapeutic Focus

ImQuest Life Sciences will become a leader in the
development of exciting new drugs for unmet medical
needs throughout the world.

Topical Microbicides

"The introduction of a microbicide with 60% efficacy, introduced into 73 low-income countries, could avert 2.5 million HIV infections over three years in women, men and infants."

Development of Topical Microbicides to Prevent the Transmission of HIV and Other Sexually Transmitted Organisms:   The development of topical microbicides for use in the prevention of the sexual transmission of HIV has become a high priority of the National Institutes of Health (NIH) and World Health Organization (WHO). Our laboratories have been at the forefront of topical microbicide development over the past decade. ImQuest’s microbicide development program utilizes a wide range of microbiological, biochemical and molecular technologies to assess the activity of agents against HIV and other sexually transmitted organisms, define the precise mechanism of action of potential microbicides using assays that closely mimic the microbicide environment, and analyze the potential toxicity of a potential microbicide. Potential microbicides will be evaluated for activity against R5 tropic strains of HIV since these are the strains that are predominantly transmitted sexually.  This includes laboratory and clinical strains in established and primary cells, respectively.  If found to be active, the compound will be evaluated in the presence of mucin, which simulates the mucopolysaccharides present in the vaginal and anal vaults, and at various pH levels to further mimic the extracellular milieu required for the topical transmission of HIV. Simulated and authentic seminal and vaginal fluids are also used in the evaluations to best mimic the environment in which the test compounds must function.  Secondary evaluations include specific mechanism of action assays to identify the class of the inhibitor.  Additional range of action assays will also be performed to assess the inhibitory potential of a compound against other viral and bacterial pathogens that might be present during the sexual transmission of HIV.

HIV

Evaluation of HIV Efficacy

• Standard assays in established and primary cell lines with laboratory and clinical strains of virus to include wild type and resistant strains, clades found throughout the world and strains with different tropisms (X4, R5 and X4/R5)
• Assays determining efficacy against cell-free and cell-associated virus
• Evaluation of CD4-dependent and CD4-independent transmission

Mechanism of HIV Action

• Entry inhibition to include attachment, fusion and entry through co-receptors
• Direct virus inactivation (virucidal activity)
• Reverse transcriptase inhibition

Range of HIV Action

• HSV-2 efficacy
• Hepatitis B and C efficacy
• Efficacy against organisms causing bacterial vaginosis and vaginal yeast
• Efficacy against Chlamydia, Gonorrhea and Trichomoniasis vaginalis

Evaluations Performed Under Microbicide Relevant Conditions

• Semen, seminal fluid or vaginal fluid
• Mucin
• Shifts in pH
• Time dependent and addition assays to mimic the coitus event
• Microbicide Transmission and Sterilization Assay (MTSA)

Toxicity Assays

• Evaluations in representative cell lines in parallel with efficacy assays
• Evaluation in cervical, vaginal and rectal specific cell lines
• Evaluation in epivaginal tissue
• Evaluation to the normal vaginal flora, Lactobacillus

Combination Evaluations

• Combination assays in relevant cell types, against relevant viruses, for relevant durations of time

 Resistance Selection

• Selection of resistance virus to a potential microbicide
• Evaluation of efficacy of a potential microbicide to resistant viruses

Ex Vivo Evaluations

• Vaginal and rectal cervical explants will be utilized to evaluate both efficacy and toxicity of a potential microbicide.

Formulation

• Determination of optimal formulations for candidate microbicides
• Antiviral efficacy and cellular toxicity evaluations of candidate microbicides

Animal Models

• Rabbit vaginal irritation model
• Non-human primate models for efficacy


Other STI Causing Organisms

Bacteria and Fungi – Minimal Inhibitory Concentration Determinations

• Chlamydia
• Gonnorrhea
• Trichomoniasis vaginalis
• Gardnerella vaginalis
• Bacterioides fragilis
• Candida albicans

Other Viruses

• HSV-2
• Hepatitis B
• Hepatitis C

Although the target for a microbicide is HIV, as part of our development program we evaluate its activity against other STI-causing organisms and organisms that may potentiate infection by HIV.

Minimal Inhibitory Concentration Determinations (MICs) are performed under NCLSI standards and practices to determine the activity of a potential microbicide. Broth and/or agar dilution is utilized for MIC determinations against the following bacterial and fungal organisms:

• Gonnorrhea
• Gardnerella vaginalis
• Bacterioides fragilis
• Candida albicans

MICs for Chlamydia and Trichomonaisis vaginalis are determined by inclusion body staining and motility, respectively.