Genentech, Inc.

Chiron Corporation

Marcus D Ballinger

James A Wells

Wayne J Fairbrother

Jennifer T Jones

Mark X Sliwkowski

W Michael Kavanaugh

Michael Kavanaugh

Mark S Sliwkowski

The present invention provides heregulin variants that are capable of binding an ErbB receptor. Included in the invention are variants of human heregulins, and, in particular, variants of human heregulin-&#x3b2;1 having enhanced affinity for the ErbB-3 and ErbB-4 receptors. These variants include at least one amino acid substitution and can include further modifications. The invention also provides nucleic acid molecules encoding heregulin variants and related vectors, host cells, pharmaceutical compositions, and methods.

Heregulin variants

The invention relates to compositions and methods for inhibiting cell proliferation, especially angiogenesis. The invention specifically relates to fusions of the extracellular domain of a fibroblast growth factor receptor (FGFR) with a heterologous oligomerization domain, such as that contained in an immunoglobulin, to provide potent FGFR antagonists.

Fibroblast growth factor receptor-immunoglobulin fusion

Peptidic compositions having FGF receptor affinity, as well as fusion proteins and oligomers of the same, are provided. The subject peptidic compounds are characterized by having little or no homology to naturally occurring bFGF. The subject fusion proteins include the peptidic composition linked to an oligomerization domain, either directly or through a linking group and optionally further include a heparin binding domain. The subject peptidic compositions, fusion proteins and oligomers thereof find use in a variety of applications, including both research and therapeutic applications, in which FGF receptor ligands are employed.

Synthetic peptides having FGF receptor affinity

The present invention provides heregulin variants that are capable of binding an ErbB receptor. Included in the invention are variants of human heregulins, and, in particular, variants of human heregulin-&bgr;1 having enhanced affinity for the ErbB-3 and ErbB-4 receptors. These variants include at least one amino acid substitution and can include further modifications. The invention also provides nucleic acid molecules encoding heregulin variants and related vectors, host cells, pharmaceutical compositions, and methods.

The present invention provides heregulin variants that are capable of binding an ErbB receptor. Included in the invention are variants of human heregulins, and, in particular, variants of human heregulin-.beta.1 having enhanced affinity for the ErbB-3 and ErbB-4 receptors. These variants include at least one amino acid substitution and can include further modifications. The invention also provides nucleic acid molecules encoding heregulin variants and related vectors, host cells, pharmaceutical compositions, and methods.

The bacterial serine protease, subtilisin BPN', has been mutated so that it will efficiently and selectively cleave substrates containing basic residues. Combination mutants, where Asn 62 was changed to Asp, Gly 166 was changed to Asp (N62D/G166D), and optionally Tyr 104 was changed to Asp had a larger than additive shift in specificity toward substrates containing basic residues. Suitable substrates of the variant subtilisin were revealed by sorting a library of phage particles (substrate phage) containing five contiguous randomized residues. This method identified a particularly good substrate, Asn-Leu-Met-Arg-Lys- (SEQ ID NO: 35), that was selectively cleaved in the context of a fusion protein by the N62D/G166D subtilisin variant. A particularly good substrate for N62D/G166D/Y104D would be Asn-Arg-Met-Arg-Lys- (SEQ ID NO: 76). Accordingly, these variant subtilisin are useful for cleaving fusion proteins with basic substrate linkers and processing hormones or other proteins (in vitro or in vivo) that contain basic cleavage sites.

Subtilisin variants capable of cleaving substrates containing basic

The bacterial serine protease, subtilisin BPN', has been mutated so that it will efficiently and selectively cleave substrates containing dibasic residues. A combination mutant, where Asn 62 was changed to Asp and Gly 166 was changed to Asp (N62D/G166D), had a larger than additive shift in specificity toward dibasic substrates. Suitable substrates of the variant subtilisin were revealed by sorting a library of phage particles (substrate phage) containing five contiguous randomized residues. This method identified a particularly good substrate, Asn-Leu-Met-Arg-Lys-, that was selectively cleaved in the context of a fusion protein by the N62D/G166D subtilisin variant. Accordingly, this variant subtilisin may be useful for cleaving fusion proteins with dibasic substrate linkers and processing hormones or other proteins (in vitro or in vivo) that contain dibasic cleavage sites.

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Burlingame, CA, United States of America

Marcus D Ballinger