A Phase II, Multicentric, Randomized, Double-Blind, Placebo-Controlled, Proof of Concept Study of Efficacy and Safety of Rifamycin SV-MMX 600 mg Tablets Administered Three or Two Times Daily to Patients With Diarrhea-Predominant Irritable Bowel Syndrome.

Introduction: Treatment with nonresorbable antibiotics is effective in diarrhea-predominant irritable bowel syndrome (IBS-D). Multimatrix (MMX) formulations ensure targeted drug delivery to the mid-distal small bowel and colon-traditionally considered the origin of IBS symptoms. To assess the efficacy of rifamycin SV-MMX for the treatment of IBS-D.

The Dual Androgen Receptor and Glucocorticoid Receptor Antagonist CB-03-10 as Potential Treatment for Tumors that have Acquired GR-mediated Resistance to AR Blockade.

CB-03-10 (cortexolone 17α-valerate-21-propionate) is a synthetic steroidal compound derived from cortexolone (11-deoxycortisone), an intermediate in cortisol biosynthesis. Characterization of the activity of CB-03-10 and its main related compound CB-03-05 (cortexolone 17α-valerate) included binding to the androgen and glucocorticoid receptors (AR and GR), antagonism of AR and GR transcriptional activities, and screening for antitumor activity across a selected panel of human prostate and in triple-negative breast cancer cell lines. CB-03-10 cytotoxic activity in these cancer cell lines was in the low micromolar range and was primarily associated with induction of the apoptotic cascade via activation of caspases.

Efficacy and Safety of Topical Clascoterone Cream, 1%, for Treatment in Patients With Facial Acne: Two Phase 3 Randomized Clinical Trials.

Importance: Acne is a common, multifactorial skin condition, and treatments with novel mechanisms have been elusive.

Objective: To assess the safety and efficacy of clascoterone cream, 1%, a novel topical androgen receptor inhibitor, in 2 phase 3 randomized clinical trials (CB-03-01/25 and CB-03-01/26).

Design, Setting, And Participants: Two identical, multicenter, randomized, vehicle-controlled, double-blind, phase 3 studies conducted from November 2015 to April 2018 evaluated the efficacy and safety of use of clascoterone cream, 1%, in males and nonpregnant females 9 years and older with moderate or severe facial acne as scored on the Investigator's Global Assessment scale.

A Phase 2b, Randomized, Double-Blind Vehicle Controlled, Dose Escalation Study Evaluating Clascoterone 0.1%, 0.5%, and 1% Topical Cream in Subjects With Facial Acne.

Androgens play a key role in acne pathogenesis in both males and females. Clascoterone (CB-03-01, Cortexolone 17α propionate) cream is a topical anti-androgen under investigation for the treatment of acne. The results from a phase 2b dose escalating study are discussed.

Pharmacokinetic Profile, Safety, and Tolerability of Clascoterone (Cortexolone 17-alpha propionate, CB-03-01) Topical Cream, 1% in Subjects With Acne Vulgaris: An Open-Label Phase 2a Study.

Clascoterone (cortexolone 17α-propionate, CB-03-01) 1% cream, a topical, androgen receptor (AR) inhibitor under investigation for the treatment of acne vulgaris, is rapidly metabolized to cortexolone in human plasma. The primary objectives of this study were to determine the pharmacokinetic (PK) properties and adrenal suppression potential of clascoterone topical cream, 1% in subjects with acne vulgaris. Study Design: This study was an open-label, multicenter study in 42 subjects ≥12 years of age with moderate-to-severe acne (Grade 3-4 on the Investigator’s Global Assessment [IGA]), on the face, chest and/or back.

Cortexolone 17α-propionate (Clascoterone) Is a Novel Androgen Receptor Antagonist that Inhibits Production of Lipids and Inflammatory Cytokines from Sebocytes In Vitro.

Cortexolone 17α-propionate (clascoterone) is a novel topical androgen antagonist that is being analyzed for its ability to treat acne. The pathogenesis of acne is attributed to multiple factors, including altered sebum production, inflammatory processes, dysregulation of the hormone microenvironment, and the proliferation of the skin commensal bacteria, Propionibacterium acnes (P. acnes).

Rifamycin SV exhibits strong anti-inflammatory in vitro activity through pregnane X receptor stimulation and NFκB inhibition.

Rifamycin SV (rifamycin), is a member of the ansamycin family of antimicrobial compounds which kills bacteria commonly associated with infectious diarrhea and other enteric infections. Rifamycin has been found to be effective in experimental animal models of gut inflammation and its efficacy in these settings has been attributed partially to immunomodulatory non-bactericidal activities. This study aimed to further evaluate the anti-inflammatory activities of rifamycin by analyzing its effect on two key regulators of inflammation: PXR and NFκB.

Cortexolone 17α-Propionate (Clascoterone) is an Androgen Receptor Antagonist in Dermal Papilla Cells In Vitro.

Cortexolone 17α-propionate (clascoterone) is a novel androgen antagonist that is currently being analyzed in a large phase 2 clinical trial for the topical treatment of androgenetic alopecia (AGA). While the pathogenesis of AGA is still debated, the consensus is that AGA is an androgen-dependent hair disorder with strong genetic links, and that the testosterone metabolite, dihydrotestosterone (DHT), plays a causal role in its development. DHT binds to the androgen receptor (AR) in scalp dermal papilla cells (DPC) to induce AR-mediated transcription of genes that contribute to AGA in genetically predisposed individuals.

Anti-inflammatory and immunomodulatory activities of rifamycin SV.

There have been several reports showing convincing evidence for non-bactericidal activities of the rifamycin antibiotics. In particular, the parent compound rifamycin SV has been employed in a limited number of cases to treat rheumatoid arthritis. Moreover, rifamycin SV and its derivative rifaximin have been found to be effective in experimental animal models of gut inflammation.

TLR9-independent activation of B lymphocytes by bacterial DNA.

The intracellular Toll-like receptor 9 (TLR9) is unique in its ability to recognize single-stranded DNA unmethylated at CpG motifs. Work from this laboratory showed that plasmid DNA is spontaneously internalized in B lymphocytes. This event is followed by the upregulation of costimulatory molecules and the acquisition of antigen presenting function by these cells.

The cooperation between two CD4 T cells induces tumor protective immunity in MUC.1 transgenic mice.

Immunity and tumor protection in mice transgenic for human MUC.1, a glycoprotein expressed in the majority of cancers of epithelial origin in humans, were induced by vaccination with B lymphocytes genetically programmed to activate MUC.1-specific CD4 T cells.

In utero DNA immunisation. Immunity over tolerance in fetal life.

The function and plasticity of the developing immune system during embryonic life has been central to immunological thinking for half a century. A classical view is that antigen encountered during fetal life induces a state of acquired immunological tolerance. However, the ability to develop T cell immune responses during the perinatal period would be of great importance against intracellular pathogens.

CD4 T cells in tumor immunity.

T cell immunity is the key to protective immune responses against tumors. Traditionally, this function has been ascribed to CD8 T lymphocytes with cytotoxic activity, which are restricted by MHC class I molecules. In recent years the realization that CD4 T cells can also play a relevant role in protective anti-tumor responses has received growing attention.

CD8 T cell priming by B lymphocytes is CD4 help dependent.

While it is generally accepted that B lymphocytes can present antigen and activate CD4 T cells, priming of CD8 T cells by B lymphocytes remains controversial. Recently, we showed that mice injected with genetically programmed B lymphocytes generate antigen specific CD4 and CD8 T cell responses in vivo that could also be induced in mice lacking functional dendritic cells. To gain further insights into the requirements for T cell priming by antigen-presenting B lymphocytes, in vitro experiments were performed using ovalbumin (OVA) and OVA-specific TCR-transgenic CD4 and CD8 T cells.

Genetically programmed B lymphocytes are highly efficient in inducing anti-virus protective immunity mediated by central memory CD8 T cells.

The hallmarks of specific T cell immunity include proliferative expansion, acquisition of effector function and memory T cell formation. Here, we used priming with B lymphocytes transgenic for the dominant epitope (NP366-374) of the influenza virus nucleoprotein, to study the characteristics of the CD8 T cell memory response in C57Bl/6 mice and elucidate which subset of CD8 T cells memory mediates protection from disease. We found that (i) the size of the memory CTL response is independent of the priming dose and is similar to that induced by the live virus, (ii) priming with a low dose (3 x 10(2)cells/inoculum) of transgenic B lymphocytes confers a protective memory CTL response, and (iii) protection from disease is mediated by central memory (T(CM)) CD8 T cells.

B lymphocytes as antigen-presenting cell-based genetic vaccines.

Inoculation of plasmid DNA is a simple way to immunize, but it is characterized by low immunogenicity, which has hampered the development of effective DNA vaccines for human use. Here, we discuss how poor immunogenicity can be solved and present our proposal: genetically programmed B lymphocytes as antigen-presenting cell (APC) vaccines. First, we demonstrate that mature B lymphocytes take up plasmid DNA spontaneously, i.

T cell immunity using transgenic B lymphocytes.

Adaptive immunity exists in all vertebrates and plays a defense role against microbial pathogens and tumors. T cell responses begin when precursor T cells recognize antigen on specialized antigen-presenting cells and differentiate into effector cells. Currently, dendritic cells are considered the only cells capable of stimulating T lymphocytes.

The role of relB in regulating the adaptive immune response.

Dendritic cells (DCs), which represent a key type of antigen-presenting cell (APC), are important for the development of innate and adaptive immunity. DCs are involved in T cell activation in at least two main ways: priming via direct processing/presentation of soluble antigen taken up from the microenvironment (conventional priming), and processing/presentation of antigen released from other cells (cross-priming). relB, a component of the NF-kappaB complex of transcription factors, is a critical regulator of the differentiation of DCs.

Role of T cell help and endoplasmic reticulum targeting in protective CTL response against influenza virus.

We report on the induction of primary and long-term memory cytotoxic T lymphocyte (CTL) responses against the nucleoprotein of the influenza virus A/PR8/34 in mice immunized with plasmid DNA targeted to B lymphocytes in the spleen. We found that the magnitude of the CTL response and the size of the pool of memory CTL was greater when the CTL response was induced in presence of T cell help. Interestingly, immunization with a signal sequence-competent transgene was markedly superior to immunization with a transgene lacking the endoplasmic reticulum (ER) targeting sequence, in inducing CTL.

CD4 T cell priming in dendritic cell-deficient mice.

Bone marrow (BM) chimeras (BMC) generated from mice carrying a null (-/-) mutation in the relB gene of the NF-kappaB family represent an ideal model for in vivo studies on the role of dendritic cells (DC) in the adaptive immune response. The spleen and lymph nodes (LN) of relB(-/-) BMC contain a small number of residual DC, mainly CD8alpha(+), that fail to up-regulate MHC class II and co-stimulatory molecules after stimulation in vitro. Moreover, residual spleen DC of relB(-/-) BMC have a 4-fold decrease in the ability to uptake and process soluble model antigen, ovalbumin (OVA), and failed to prime CD4 and CD8 T cells in vitro and in vivo.