Amgen Inc.

Fei Xiong

Colin V Gegg

Karen C Sitney

Kenneth William Walker

Leslie Phillip Miranda

Hailing Hsu

Hosung Min

Jr Colin V Gegg

Collin Gegg

Disclosed is a process for preparing a pharmacologically active compound, in which at least one internal conjugation site of an Fc domain sequence is selected that is amenable to conjugation of an additional functional moiety by a defined conjugation chemistry through the side chain of an amino acid residue at the conjugation site. An appropriate amino acid residue for conjugation may be present in a native Fc domain at the conjugation site or may be added by insertion (i.e., between amino acids in the native Fc domain) or by replacement (i.e., removing amino acids and substituting different amino acids). In the latter case, the number of amino acids added need not correspond to the number of amino acids removed from the previously existing Fc domain. This technology may be used to produce useful compositions of matter and pharmaceutical compositions containing them. A DNA encoding the inventive composition of matter, an expression vector containing the DNA, and a host cell containing the expression vector are also disclosed.

Modified Fc molecules

The present invention concerns therapeutic agents that modulate the activity of TALL-1. In accordance with the present invention, modulators of TALL-1 may comprise an amino acid sequence DzLzwherein zis an amino acid residue and zis threonyl or isoleucyl. Exemplary molecules comprise a sequence of the formulae wherein the substituents are as defined in the specification. The invention further comprises compositions of matter of the formula(X)&#x2014;V&#x2014;(X)wherein V1 is a vehicle that is covalently attached to one or more of the above TALL-1 modulating compositions of matter. The vehicle and the TALL-1 modulating composition of matter may be linked through the N- or C-terminus of the TALL-1 modulating portion. The preferred vehicle is an Fc domain, and the preferred Fc domain is an IgG Fc domain.

Peptides and related molecules that bind to TALL-1

The present invention provides a means for increasing the serum half-life of a selected biologically active agent by utilizing transthyretin (TTR) as a fusion partner with a biologically active agent. Specifically, the present invention provides substantially homogenous preparations of TTR (or a TTR variant)-biologically active agent fusions and PEG-TTR (PEG-TTR variant)-biologically active agent fusions. As compared to the biologically active agent alone, the TTR-biologically active agent fusion and/or PEG-TTR-biologically active agent fusion has substantially increased serum half-life.

Transthyretin variants

The present invention concerns therapeutic agents that modulate the activity of TALL-1. In accordance with the present invention, modulators of TALL-1 may comprise an amino acid sequence DzLzwherein zis an amino acid residue and zis threonyl or isoleucyl. Exemplary molecules comprise a sequence of the formulae wherein the substituents are as defined in the specification. The invention further comprises compositions of matter of the formula(X)-V-(X)wherein V1 is a vehicle that is covalently attached to one or more of the above TALL-1 modulating compositions of matter. The vehicle and the TALL-1 modulating composition of matter may be linked through the N- or C-terminus of the TALL-1 modulating portion. The preferred vehicle is an Fc domain, and the preferred Fc domain is an IgG Fc domain.

The present invention concerns compositions of matter, for example, but not limited to, modified antibodies, in which one or more biologically active peptides are incorporated into a loop region of a non-terminal domain of an immunoglobulin Fc domain.

The present invention concerns therapeutic agents that modulate the activity of TALL-1. In accordance with the present invention, modulators of TALL-1 may comprise an amino acid sequence DzLzwherein zis an amino acid residue and zis threonyl or isoleucyl. Exemplary molecules comprise a sequence of the formulae wherein the substituents are as defined in the specification. The invention further comprises compositions of matter of the formula(X)&#x2014;V&#x2014;(X)wherein Vis a vehicle that is covalently attached to one or more of the above TALL-1 modulating compositions of matter. The vehicle and the TALL-1 modulating composition of matter may be linked through the N- or C-terminus of the TALL-1 modulating portion. The preferred vehicle is an Fc domain, and the preferred Fc domain is an IgG Fc domain.

The present invention concerns molecules and a process in which one or more biologically active peptides are incorporated into an Fc domain. In this invention, pharmacologically active compounds may be prepared by a process comprising (a) selecting at least one peptide that modulates the activity of a protein of interest; and (b) preparing a pharmacologic agent comprising an amino acid sequence of the selected peptide in a loop region of an Fc domain. This process may be employed to modify an Fc domain that is already linked through an N- or C-terminus or sidechain to a peptide or to a polypeptide (e.g., etanercept). This process may also be employed to modify an Fc domain that is part of an antibody (e.g., adalimumab, epratuzumab, infliximab, Herceptin&#xae;, and the like). In this way, different molecules can be produced that have additional functionalities, such as a binding domain to a different epitope or an additional binding domain to the precursor molecule's existing epitope. The peptide can be selected, for example, by phage display,display, ribosome display, RNA-peptide screening, yeast-based screening, chemical-peptide screening, rational design, or protein structural analysis.

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Thousand Oaks, CA, United States of America

Fei Xiong