Loading patent…
AssigneeGenentech, Inc.
InventorsJin-an Jiao, Hing C. Wong, Esperanza Liliana Nieves, Luis A. Mosquera
Estimating the term…
The invention includes antibodies that provide superior anti-coagulant activity by binding native human TF with high affinity and specificity. Antibodies of the invention can effectively inhibit blood coagulation in vivo. Antibodies of the invention can bind native human TF, either alone or present in a TF:FVIIa complex, effectively preventing factor X or FIX binding to TF or that complex, and thereby reducing blood coagulation. Preferred antibodies of the invention specifically bind a conformational epitope predominant to native human TF, which epitope provides an unexpectedly strong antibody binding site. Also provided are humanized antibodies and fragments thereof that bind to the TF.
An anti-TF antibody comprising a light chain, wherein the light chain comprises:
An anti-TF antibody comprising:
An anti-TF antibody comprising:
An anti-TF antibody comprising a light chain, wherein the light chain comprises:
An anti-TF antibody comprising:
Dependencies are inferred from the claim text.
Drawings are temporarily unavailable. Open the PDF at USPTO
From the US filing history. Foreign family members aren’t listed.
Against material from animals or humans: against blood coagulation factors
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Igs containing Ig-regions, -domains or -residues form different species: igs with modifications in the FR-residues only
Medicinal preparations containing antigens or antibodies: comprising antibodies
Term ended 21 Nov 2021 (estimated)
1. Field of the Invention
The present invention relates to novel human tissue factor antibodies and methods of using the antibodies to inhibit tissue factor-related functions such as blood coagulation, angiogenesis, tumor metastasis, and inflammation. In particular, the invention relates to novel antibodies that can specifically bind native human tissue factor with high affinity and prevent factor X or factor IX binding and activation. The antibodies of the invention are useful for a variety of applications, particularly for reducing blood coagulation in vivo.
2. Background
FIGS. 1A and 1B shows the nucleic acid (SEQ ID NOS: 1 and 3) and amino acid (SEQ ID NOS:2 and 4) sequences of light chain and heavy chain variable regions of H36.D2.B7 with hypervariable regions (CDRs or Complementarity Determining Regions) underlined (single underline for nucleic acid sequences and double underline for amino acid sequences) (SEQ ID NOS: 5-10, respectively, in order of appearance).
FIG. 2 shows association (Ka) and disassociation (Kd) constants of anti-tissue factor antibodies as determined by ELISA or BIACore analysis.
FIG. 3 shows inhibition of TF:FVIIa complex mediated FX activation by pre-incubation with anti-tissue factor antibodies.
As discussed above, preferred antibodies of the invention exhibit substantial affinity for native human TF. In particular, preferred antibodies of the invention exhibit an association constant (Ka, M−1) for native human TF of at least about 1×108 as determined by surface plasmon analysis (particularly, BIACore analysis in accordance with the procedures of Example 1 which follows), more preferably at least about 5×108 as determined by surface plasmon analysis, still more preferably a Ka (Ka, M−1) for native human TF of at least about 1×1010 as determined by surface plasmon resonance analysis. Such substantial binding affinity of antibodies of the invention contrast sharply from much lower binding affinities of previously reported antibodies.
In this regard, a quite low of effective concentration of an antibody of the invention can be employed, e.g. a relatively low concentration of antibody can be employed to inhibit TF function as desired (e.g. at least about 95, 98 or 99 percent inhibition) in an in vitro assay such as described in Example 3 which follows.
The preferred antibodies are also highly specific for native human TF, and preferably do not substantially bind with non-native TF. Preferred antibodies do not substantially bind non-native TF or other immunologically unrelated molecules as determined, e.g. by standard dot blot assay (e.g. no or essentially no binding to non-native TF visually detected by such dot blot assay). References herein to “non-native TF” mean a naturally-occurring or recombinant human TF that has been treated with a chaotropic agent so that the TF is denatured. Typical chaotropic agents include a detergent (e.g. SDS), urea combined with dithiothreotol or β-mercaptoethanol; guanidine hydrochloride and the like. The H36, H36.D2 or H36.D2.B7 antibody does not substantially bind to such non-native TF. See, for instance, the results of Example 8 which follows and is a dot blot assay.