The present invention relates to engineered multivalent and multispecific binding proteins, methods of making, and specifically to their uses in the prevention, diagnosis, and/or treatment of disease.

Dual variable domain immunoglobulins and uses thereof

Antibodies are engineered by replacing one or more amino acids of a parent antibody with non cross-linked, highly reactive cysteine amino acids. Antibody fragments may also be engineered with one or more cysteine amino acids to form cysteine engineered antibody fragments (ThioFab). Methods of design, preparation, screening, and selection of the cysteine engineered antibodies are provided. Cysteine engineered antibodies (Ab), optionally with an albumin-binding peptide (ABP) sequence, are conjugated with one or more drug moieties (D) through a linker (L) to form cysteine engineered antibody-drug conjugates having Formula I: Ab-(L-D)p I where p is 1 to 4. Diagnostic and therapeutic uses for cysteine engineered antibody drug compounds and compositions are disclosed.

Cysteine engineered antibodies and conjugates

The invention relates to the discovery of novel soluble neutral active Hyaluronidase Glycoproteins (sHASEGPs), methods of manufacture, and their use to facilitate administration of other molecules or to alleviate glycosaminoglycan associated pathologies. Minimally active polypeptide domains of the soluble, neutral active sHASEGP domains are described that include asparagine-linked sugar moieties required for a functional neutral active hyaluronidase domain. Included are modified amino-terminal leader peptides that enhance secretion of sHASEGP. The invention further comprises sialated and pegylated form of a recombinant sHASEGP to enhance stability and serum pharmacokinetics over naturally occurring slaughterhouse enzymes. Further described are suitable formulations of a substantially purified recombinant sHASEGP glycoprotein derived from a eukaryotic cell that generate the proper glycosylation required for its optimal activity.

Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases

An antibody binding to IGF-IR and inhibiting the binding of IGF-I and IGF-II to IG-RI which is characterized in that said antibody is of human IgG1 isotype, and shows a ratio of inhibition of the binding of IGF-I to IGF-IR to the inhibition of binding of IGF-II to IGF-IR of 1:3 to 3:1, and induces celle death of 20% or more cells of a preparation of IGF-IR expressing cells after 24 hours at a concentration of said antibody of 100 nM by ADCC; has improved properties in antitumor therapy.

Antibodies against insulin-like growth factor i receptor and uses thereof

The present invention relates to engineered multivalent and multispecific binding proteins, methods of making, and specifically to their uses in the prevention and/or treatment of acute and chronic inflammatory and other diseases

Dual variable domain immunoglobin and uses thereof

Provided are soluble neutral active Hyaluronidase Glycoproteins (sHASEGP's), methods of manufacture, and their use to facilitate administration of other molecules or to alleviate glycosaminoglycan associated pathologies. Minimally active polypeptide domains of the soluble, neutral active sHASEGP domains are described that include asparagine-linked sugar moieties required for a functional neutral active hyaluronidase domain. Included are modified amino-terminal leader peptides that enhance secretion of sHASEGP. Sialated and pegylated forms of the sHASEGPs also are provided. Methods of treatment by administering sHASEGPs and modified forms thereof also are provided.

Soluble hyaluronidase glycoprotein (shasegp), process for preparing the same, uses and pharmaceutical compositions comprising thereof

Soluble PH20 polypeptides are provided, including extended soluble PH20 polypeptides, and uses thereof. Also provided are other C-terminally truncated PH20 polypeptides and partially deglycosylated PH20 polypeptides and uses thereof.

Extended soluble ph20 polypeptides and uses thereof

5075 Many tumors are associated with elevated levels of hyaluronan (HA). Through interaction with other extracellular matrix molecules, HA perturbs the delivery of cytostatic agents. Bovine forms of hyaluronidase, an HA degrading enzyme, have shown promise clinically as a chemosensitizing agent in a number of malignancies, but suffered immunologic and pharmacokinetic limitations. We therefore engineered a recombinant soluble form of human hyaluronidase (rHuPH20). The highly purified rHuPH20 enzyme lacked any gross or histologic toxicity across a very broad therapeutic range, and failed to elicit neutralizing antibodies in non human primates. rHuPH20 enhanced the dispersion of molecules up to 200nm in diameter in a dose dependent fashion, and increased hydraulic conductivity over 10 fold. These effects were fully reversible within 24 hours post injection. The enzyme itself was also systemically bioavailable, facilitating the dispersion of indicator dyes injected at distal sites without altering vascular permeability. Application of rHuPH20 to tumor cells in vitro effectively removed pericellular hyaluronan, which rapidly regenerated upon its removal from the culture media. Application of rHuPH20 to human xenograft models resulted in a significant reduction in tumor interstitial fluid pressure within 1 hour of administration. As increased interstitial fluid pressure is a key factor limiting bulk fluid flow in solid tumors, we conclude that recombinant human PH20 warrants testing as an adjunct to increase the therapeutic index of cytostatic regimens.

Effects of recombinant human PH20 (rHuPH20) on interstitial matrices: creating a favorable environment for the delivery of cytostatic agents

The invention relates to the discovery of a novel Chondroitinase Glycoproteins (CHASEGP's), methods of manufacture, and potential uses in conditions where removal of chondroitin sulfates may be of therapeutic benefit. Chondroitinase Glycoproteins require both a substantial portion of the catalytic domain of the CHASEGP polypeptide and asparagine-linked glycosylation for optimal chondroitinase activity. The invention also includes carboxy-terminal deletion variants of CHASEGP that result in secreted variants of the protein to facilitate manufacture of a recombinant CHASEGP. Further described are suitable formulations of a substantially purified recombinant CHASEGP glycoprotein derived from a eukaryotic cell that generate the proper glycosylation required for its optimal activity. CHASEGP is useful for the degradation of glycosaminoglycans and chondroitin sulfate proteoglycans under clinical conditions where their removal is of therapeutic value.

Louis H. Bookbinder

Papers

Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases

Soluble hyaluronidase glycoprotein (shasegp), process for preparing the same, uses and pharmaceutical compositions comprising thereof

Extended soluble ph20 polypeptides and uses thereof

Effects of recombinant human PH20 (rHuPH20) on interstitial matrices: creating a favorable environment for the delivery of cytostatic agents

Human chondroitinase glycoprotein (chasegp), process for preparing the same, and pharmaceutical compositions comprising thereof