Boston Biomedical Research Institute

Other

Victor A Raso

Henry P Paulus

Katherine Sheldon

The present invention relates, in part, to agents for binding and/or inactivating native ghrelin. These agents include those that specifically bind and/or cleave octanoylated native ghrelin. Such agents include antibodies and enzymes. The agents also include those that can be used to generate antibodies that specifically bind and/or cleave octanoylated native ghrelin. Compositions that include the agents are also provided. Further provided are methods of producing and using the agents and compositions thereof. For instance, the agents and compositions can be used to reduce or eliminate the hunger response activity of octanoylated native ghrelin. Therefore, the agents, compositions and methods provided can be used to suppress appetite and/or treat obesity. In addition, the agents, compositions and methods can be used to treat any disease associated with or caused by ghrelin (e.g., Prader-Willi Syndrome).

Isolated monoclonal antibody or antigen-binding fragment that cleaves octanoylated native ghrelin

Disclosed are bispecific antibodies comprising a first antibody binding specificity which confers the ability of the bispecific antibody to cross the blood-brain barrier, and a second antibody specificity conferring the ability of the bispecific antibody to bind to a &#x3b2;-amyloid epitope. Also disclosed are methods for inhibiting the formation of &#x3b2;-amyloid plaques in the brain of a human, or promoting the disaggregation of a preformed &#x3b2;-amyloid plaque. Such methods recite the administration of a bispecific antibody.

Immunological control of &#x3b2;-amyloid levels in vivo

Provided is a simple and safe immunization procedure to reduce cancer incidence and increase longevity by modulating IGF-1 levels in the body. Described are cancer preventive vaccines and methods that elicit circulating antibodies specific to insulin-like growth factor 1 (IGF-1) in the body. Many cancers will be less likely to occur and spread in the absence or reduced levels of the stimulatory signals provided by IGF-1. Longevity also can be extended by immunologically lowering the level of bioavailable IGF-1 in adult animals. This prolongation of lifespan resulting from lower IGF-1 levels is produced independently of the inhibitory effects on carcinogenesis. However, the two IGF-1-mediated processes are linked mechanistically. Methods of active and passive immunization to suppress IGF-1 activity are included. Also described are methods for increasing longevity or reducing one or more symptoms of aging in a warm-blooded animal comprising administering anti-IGF-1 antibodies such that IGF-1 is inactivated or suppressed or administering IGF-1 antigen such that the animal produces endogenous antibodies to IGF-1.

Immunological modulation of insulin-like growth factor 1 for cancer prevention/treatment and prolonging longevity

Disclosed are antibodies which catalyze hydrolysis of &#x3b2;-amyloid. Antibodies generated are characterized by the amide linkage which they hydrolyze. Methods of generating the antibodies by using &#x3b2;-amyloid peptides which incorporate transition state analogs are also provided. Also disclosed is a vectorized antibody which is characterized by the ability to cross the blood brain barrier, and is further characterized by the ability to catalyze the hydrolysis of &#x3b2;-amyloid. The vectorized antibody can take the form of bispecific antibody, which has a first specificity for the transferrin receptor and a second specificity for a taransition state adopted by &#x3b2;-amyloid hydrolysis.

Disclosed are bispecific antibodies comprising a first antibody binding specificity which confers the ability of the bispecific antibody to cross the blood-brain barrier, and a second antibody specificity conferring the ability of the bispecific antibody to bind to a &#x3b2;-amyloid epitope. Also disclosed are methods for inhibiting the formation of &#x3b2;-amyloid plaques in the brain of a human, of promoting the disaggregation of a preformed &#x3b2;-amyloid plaque. Such methods recite the administration of a bispecific antibody.

Disclosed are antibodies which catalyze hydrolysis of &bgr;-amyloid. Antibodies generated are characterized by the amide linkage which they hydrolyze. Methods of generating the antibodies by using &bgr;-amyloid peptides which incorporate transition state analogs are also provided. Also disclosed is a vectorized antibody which is characterized by the ability to cross the blood brain barrier, and is further characterized by the ability to catalyze the hydrolysis of &bgr;-amyloid. The vectorized antibody can take the form of a bispecific antibody, which has a first specificity for the transferrin receptor and a second specificity for a transition state adopted by &bgr;-amyloid during hydrolysis.

Immunological control of &bgr;-amyloid levels in vivo

Disclosed are methods for the production of second generation catalytic antibodies. The disclosed methods offer a variety of advantages relative to prior art techniques. For example, the methods of the present invention do not require prior identification of the active site of an enzyme, the activity of which is desired in the catalytic antibody. Additionally, the disclosed methods enable the production of antibodies which catalyze chemical reactions which do not occur in nature.

Anti-idiotype vaccines to elicit catalytic antibodies

The method of the present invention employs a hybrid reagent comprising a first portion (i.e., a cell-targeting portion) which binds to cell surfaces coupled to a second portion (i.e., a toxin-binding portion) which binds to, or has bound to it, an endosomally active domain of DT and releases the endosomally active domain of DT in response to the low pH in endosomal vesicles of cells. Thus, the second portion of the hybrid reagent binds an endosomally active domain directly (e.g., an antibody which binds to all or a portion of the T domain of DT) or indirectly (e.g., an antibody which binds to the R domain of a moiety in which the R domain of DT is coupled to the T domain of DT). A second endosomally active domain of DT, which is different from the first endosomally active domain of DT, is delivered to the same endosomal vesicles separately. The independent endosomally active domains of DT are not toxic to cells until they meet within the endosomes. Thus, the therapeutic window of the binary toxin described herein is much greater than current toxin delivery systems, which generally retain collateral toxicity, even when undelivered.

Method for delivering functional domains of diphtheria toxin to a

Hybrid reagents comprising a first portion having an affinity for a cellular target and a second portion having an affinity for a bioactive molecule are described, said hybrid reagents being capable of selectively releasing the bioactive molecule in response to a change in pH. The hybrid reagents of the present invention can be used diagnostically or therapeutically.

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Brookline, MA, United States of America

Victor A Raso