A ubiquitous cell adhesion receptor, CD44, preferentially binds hyaluronan, a polysaccharide macromolecule that is present in most extracellular matrices. Hyaluronan molecules have large hydrodynamic volumes that entrap substantial amounts of water and can therefore control tissue hydration (swelling). CD44 is overexpressed by synovial cells and leukocytes, and hyaluronan is overproduced in the rheumatoid synovium and in other inflammatory sites. Nevertheless, the role of the CD44-hyaluronan interaction during inflammation is unclear. Our evidence shows that the CD44 receptor plays a critical role in governing the migration of inflammatory leukocytes into the extravascular compartment of the synovium in murine arthritis. An anti-CD44 antibody induces a rapid loss of CD44 from both leukocytes and synovial cells and displays an inhibitory effect on cell-extracellular matrix interactions in the synovium. As a result, the administration of such an antibody abrogates tissue swelling and leukocyte infiltration, two major components of inflammation.

Pathogenic immunoglobulin G (IgG) autoantibodies characterize some human autoimmune diseases; their high concentration and long half-life are dependent on recycling by the neonatal Fc receptor (FcRn). Inhibition of FcRn is an attractive new treatment concept for IgG-mediated autoimmune diseases. Rozanolixizumab (UCB7665; CA170_01519.g57 IgG4P) is an anti-human FcRn monoclonal antibody. In cynomolgus monkeys, rozanolixizumab reduced IgG (maximum 75 to 90% by about day 10), was well tolerated, and did not increase risk of infection. We also report a first-in-human, randomized, double-blind, placebo-controlled, dose-escalating study of intravenous (IV) or subcutaneous (SC) rozanolixizumab in healthy subjects (NCT02220153). The primary objective was to evaluate safety and tolerability. Secondary objectives were assessment of rozanolixizumab pharmacokinetics and pharmacodynamics, including effects on circulating IgG concentrations. Forty-nine subjects were randomized to receive rozanolixizumab ( = 36) or placebo ( = 13) across six cohorts. The first three cohorts received IV doses, and the subsequent three cohorts received SC doses, of rozanolixizumab 1, 4, or 7 mg/kg ( = 6 for each cohort; plus = 7 or 6 for placebo, respectively). The most frequent treatment-emergent adverse event [TEAE; headache, 14 of 36 (38.9%) subjects] was dose-dependent and more prominent after IV administration. Severe TEAEs occurred in four subjects, all in the highest-dose IV group [headache ( = 3) and back pain ( = 1)]. Rozanolixizumab pharmacokinetics demonstrated nonlinear increases with dose. There were sustained dose-dependent reductions in serum IgG concentrations (IV and SC rozanolixizumab). These data provide clinical evidence for the therapeutic potential of rozanolixizumab.

Abbreviations: ADA, anti-drug antibody; ADCC, antibody-dependent cellular cytotoxicity; ADME, absorption, distribution, metabolism and excretion; APC, antigen-presenting cell; AS, ankylosing spondylitis; CAPS, cropyrin-associated periodic syndromes; CD, cluster of differentiation; CDC, complement-dependent cytotoxicity; CDR, complementarity-determining region; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; CRA, cytokine release assay; CrD, Crohn disease; CRS, cytokine release syndrome; CTLA-4, cytotoxic T lymphocyte antigen-4; DAMPs, damage-associated molecular patterns; DC, dendritic cell; DTH, delayed-type hypersensitivity; EBV, Epstein Barr virus; EFD-PPND, embryo-fetal development and peri-/ post-natal development; EMA, European Medicines Agency; EPAR, European Public Assessment Report; EPO, erythropoietin; ESG, Expert Scientific Group; FDA, Food and Drug Administration; FIH, first-in-human; GD, gestation day; GLP, good laboratory practice; HED, human equivalent dose; HHV-8, human herpes virus-8; HLA, human leukocyte antigen; HSA, human serum albumin; HSP, heat shock protein; HTLV-1, human T cell leukemia virus-1; ICH, International Conference on Harmonization; IHC, immunohistochemistry; KLH, keyhole limpet hemocyanin; LCV, lymphocryptovirus; LFA-1, leukocyte function antigen-1; LPS, lipopolysaccharide; mAb, monoclonal antibody; MABEL, minimum anticipated biological effect level; MHC, major histocompatibility comlex; MoA, mechanism of action; MRSD, maximum recommended starting dose; MS, multiple sclerosis; NCE, new chemical entity; NHP, non-human primate; NK, natural killer; NLR, nod-like receptor; NOAEL, no observed adverse effect level; PAD, pharmacologically-active dose; PAMPs, pathogen-associated molecular patterns; PEG-MGDF, pegylated megakaryocyte growth and development factor; PD, pharmacodynamic; PHA, phytohemaglutinin; PK, pharmacokinetic; PML, progressive multifocal leukoencephalopathy; PsA, psoriatic arthritis; RA, rheumatoid arthritis; RMP, risk management plan; RO, receptor occupancy; RSV, respiratory syncytial virus; SBA, summary basis of approval; SLE, systemic lupus erythromatosus; SPC, summary of product characteristics; SRBC, sheep red blood cell; TCR, tissue cross reactivity; TDAR, T cell-dependent antibody response; TLR, toll-like receptor; TT, tetanus toxoid; UC, ulcerative colitis; VLA-4, very late antigen-4Most therapeutic monoclonal antibodies (mAbs) licensed for human use or in clinical development are indicated for treatment of patients with cancer and inflammatory/autoimmune disease and as such, are designed to directly interact with the immune system. A major hurdle for the development and early clinical investigation of many of these immunomodulatory mAbs is their inherent risk for adverse immune-mediated drug reactions in humans such as infusion reactions, cytokine storms, immunosuppression and autoimmunity. A thorough understanding of the immunopharmacology of a mAb in humans and animals is required to both anticipate the clinical risk of adverse immunotoxic...

The attenuation and immunogenicity of two novel Salmonella vaccine strains, Salmonella enterica serovar Typhi (Ty2 ⌬aroC ⌬ssaV, designated ZH9) and S. enterica serovar Typhimurium (TML ⌬aroC ⌬ssaV, designated WT05), were evaluated after their oral administration to volunteers as single escalating doses of 10 7 , 10 8 , or 10 9 CFU. ZH9 was well tolerated, not detected in blood, nor persistently excreted in stool. Six of nine volunteers elicited anti-serovar Typhi lipopolysaccharide (LPS) immunoglobulin A (IgA) antibody-secreting cell (ASC) responses, with three of three vaccinees receiving 10 8 and two of three receiving 10 9 CFU which elicited high-titer LPS-specific serum IgG. WT05 was also well tolerated with no diarrhea, although the administration of 10 8 and 10 9 CFU resulted in shedding in stools for up to 23 days. Only volunteers immunized with 10 9 CFU of WT05 mounted detectable serovar Typhimurium LPS-specific ASC responses and serum antibody responses were variable. These data indicate that mutations in type III secretion systems may provide a route to the development of live vaccines in humans and highlight significant differences in the potential use of serovars Typhimurium and Typhi.