Endoplasmic Reticulum-Targeted Subunit Toxins Provide a New Approach to Rescue Misfolded Mutant Proteins and Revert Cell Models of Genetic Diseases.

Many germ line diseases stem from a relatively minor disturbance in mutant protein endoplasmic reticulum (ER) 3D assembly. Chaperones are recruited which, on failure to correct folding, sort the mutant for retrotranslocation and cytosolic proteasomal degradation (ER-associated degradation-ERAD), to initiate/exacerbate deficiency-disease symptoms. Several bacterial (and plant) subunit toxins, retrograde transport to the ER after initial cell surface receptor binding/internalization.

MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function.

Background: Peripheral blood eosinophilia and lung mucosal eosinophil infiltration are hallmarks of bronchial asthma. IL-5 is a critical cytokine for eosinophil maturation, survival, and mobilization. Attempts to target eosinophils for the treatment of asthma by means of IL-5 neutralization have only resulted in partial removal of airway eosinophils, and this warrants the development of more effective interventions to further explore the role of eosinophils in the clinical expression of asthma.

Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti-IL-5 receptor alpha antibody, in a phase I study of subjects with mild asthma.

Background: Increased eosinophil levels have been linked to airway inflammation and asthma exacerbations. IL-5 is responsible for eosinophil differentiation, proliferation, and activation; IL-5 receptors are expressed on eosinophils and their progenitors, and targeting such receptors induces eosinophil apoptosis.

Objective: To evaluate the safety profile, pharmacokinetics, and pharmacodynamics of MEDI-563, a humanized mAb targeting the IL-5 receptor alpha chain.

A DeImmunized chimeric anti-C3b/iC3b monoclonal antibody enhances rituximab-mediated killing in NHL and CLL cells via complement activation.

Complement-dependent cytotoxicity (CDC) is a key mechanism of Rituximab (RTX) action in killing non-Hodgkin's lymphoma (NHL) cells both in vitro and probably in vivo. A DeImmunized, mouse/human chimeric monoclonal antibody (Mab), H17, specific for cell-associated complement C3 cleavage products, C3b and iC3b, was generated to enhance RTX-mediated killing of target cells by CDC. When NHL cell lines were treated with RTX and H17 in the presence of complement for 1 h, there was 40-70% more cell death than that observed with RTX alone.

Heteropolymers: a novel technology against blood-borne infections.

Heteropolymer (HP) technology is a novel cassette technology which is being developed for the treatment of infectious and autoimmune diseases. HPs are dual antibody conjugates, composed of a monoclonal antibody (mAb) directed against the complement receptor type 1 (CR1) on primate red blood cells (RBCs) chemically cross-linked to mAbs that recognize blood-borne antigens. Upon administration of an HP, the target is bound to its counterpart mAb in the HP and immobilized on an RBC by binding of the anti-CR1 mAb to CR1 in a complement-independent manner, forming an immune complex.

A high-affinity monoclonal antibody to anthrax protective antigen passively protects rabbits before and after aerosolized Bacillus anthracis spore challenge.

We have developed a therapeutic for the treatment of anthrax using an affinity-enhanced monoclonal antibody (ETI-204) to protective antigen (PA), which is the central cell-binding component of the anthrax exotoxins. ETI-204 administered preexposure by a single intravenous injection of a dose of between 2.5 and 10 mg per animal significantly protected rabbits from a lethal aerosolized anthrax spore challenge ( approximately 60 to 450 times the 50% lethal dose of Bacillus anthracis Ames).

Enhancement of anthrax lethal toxin cytotoxicity: a subset of monoclonal antibodies against protective antigen increases lethal toxin-mediated killing of murine macrophages.

We investigated the ability of using monoclonal antibodies (MAbs) against anthrax protective antigen (PA), an anthrax exotoxin component, to modulate exotoxin cytotoxic activity on target macrophage cell lines. Anthrax PA plays a critical role in the pathogenesis of Bacillus anthracis infection. PA is the cell-binding component of the two anthrax exotoxins: lethal toxin (LeTx) and edema toxin.

Evaluation of antigen-based heteropolymer for treatment of systemic lupus erythematosus in a nonhuman primate model.

Autoantibodies that react with double-stranded DNA (dsDNA) are a hallmark for diagnosis of systemic lupus erythematosus (SLE) and are also considered the pathogenic subset that is most associated with lupus nephritis. As an agent to remove the pathogenic dsDNA antibodies from the circulation of SLE patients, we are developing an antigen-based heteropolymer (AHP). The AHP consists of a monoclonal antibody to the complement receptor (CR1) cross-linked to salmon testis dsDNA to effect clearance of anti-DNA antibodies by binding them to erythrocyte CR1.