Altus Biologics Inc.

Althea Technologies, Inc.

Altus Pharmaceuticals Inc.

Nancy L St Clair

Alexey L Margolin

Scott L Rakestraw

Nazar K Khalaf

Bhami Shenoy

Rose A Persichetti

Nazer K Khalaf

Bhami C Shenoy

This invention relates to methods for the stabilization, storage and delivery of biologically active macromolecules, such as proteins, peptides and nucleic acids. In particular, this invention relates to protein or nucleic acid crystals, formulations and compositions comprising them. Methods are provided for the crystallization of proteins and nucleic acids and for the preparation of stabilized protein or nucleic acid crystals for use in dry or slurry formulations. The present invention is further directed to encapsulating proteins, glycoproteins, enzymes, antibodies, hormones and peptide crystals or crystal formulations into compositions for biological delivery to humans and animals. According to this invention, protein crystals or crystal formulations are encapsulated within a matrix comprising a polymeric carrier to form a composition. The formulations and compositions enhance preservation of the native biologically active tertiary structure of the proteins and create a reservoir which can slowly release active protein where and when it is needed. Methods are provided preparing stabilized formulations using pharmaceutical ingredients or excipients and optionally encapsulating them in a polymeric carrier to produce compositions and using such protein crystal formulations and compositions for biomedical applications, including delivery of therapeutic proteins and vaccines. Additional uses for-the protein crystal formulations and compositions of this invention involve protein delivery in human food, agricultural feeds, veterinary compositions, diagnostics, cosmetics and personal care compositions.

Stabilized protein crystals, formulations comprising them and methods of making them

This invention relates to methods for the stabilization, storage and delivery of biologically active macromolecules, such as proteins, peptides and nucleic acids. In particular, this invention relates to protein or nucleic acid crystals, formulations and compositions comprising them. Methods are provided for the crystallization of proteins and nucleic acids and for the preparation of stabilized protein or nucleic acid crystals for use in dry or slurry formulations. The present invention is further directed to encapsulating proteins, glycoproteins, enzymes, antibodies, hormones and peptide crystals or crystal formulations into compositions for biological delivery to humans and animals. According to this invention, protein crystals or crystal formulations are encapsulated within a matrix comprising a polymeric carrier to form a composition. The formulations and compositions enhance preservation of the native biologically active tertiary structure of the proteins and create a reservoir which can slowly release active protein where and when it is needed. Methods are provided preparing stabilized formulations using pharmaceutical ingredients or excipients and optionally encapsulating them in a polymeric carrier to produce compositions and using such protein crystal formulations and compositions for biomedical applications, including delivery of therapeutic proteins and vaccines. Additional uses for the protein crystal formulations and compositions of this invention involve protein delivery in human food, agricultural feeds, veterinary compositions, diagnostics, cosmetics and personal care compositions.

Stabilized protein crystals formulations containing them and methods of making them

Protein crystals crosslinked with a multifunctional crosslinking agent are produced that have the ability to change from an insoluble and stable form to a soluble and active form and to release protein activity at a controlled rate when a change in environment surrounding the crystals occurs. The change in environment may be a change in temperature, pH, chemical composition or shear force acting on the crystals, or a change from a concentrate to a dilute form, or a combination of the changes. The crosslinked protein crystals have a half-life activity under storage conditions greater than at least 2 times that of the soluble protein that is crystallized to form the crystals that are crosslinked, and under conditions of use have an activity similar to the soluble protein. Crosslinking is carried out by reacting a slurry of protein crystals with a multifunctional crosslinking agent such as glutaraldehyde, glyoxal, octanedialdehyde or succinaldehyde using a concentration of crosslinking agent and time for crosslinking that provides crosslinked protein crystals having the desired ability to change due to a change in environment. An epoxide multifunctional crosslinking agent may be used in combination with glutaraldehyde for crosslinking. The crosslinked protein crystals can be used for protein delivery, and may be used in cleaning agents such as detergents, pharmaceutical compositions, vaccines, personal care compositions, veterinary compositions, foods, feeds, diagnostics and decontamination formulations. Proteins used include enzymes and therapeutic or prophylactic proteins such as hormones and antibodies.

Controlled dissolution crosslinked protein crystals

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Ann Arbor, MI, United States of America

Nancy L St Clair