The assignee for this patent, patent number 8618264, is
Reporters obtained the following quote from the background information supplied by the inventors: "The present invention relates to anti-CD147 antibodies and their use as therapeutics.
"CD147 is a member of the immunoglobulin (Ig) superfamily that is expressed on a large number of different cells in a variety of tissues. It was originally named human Basigin (for basic immunogloblin superfamily) and was first cloned in about 1991. (
"CD147 is a pleiotropic molecule playing a role in fetal development, retinal function, and in T-cell maturation. It has been shown to be a cell-surface receptor for cyclophilins. It is expressed in areas of tissue remodeling: tumors, endometrium, placenta, skin and regions undergoing angiogenesis (
"Anti-CD147 antibodies have been reported. A murine antibody IgM mAbs, CBL1 (Billings et al. Hybridoma 1:303-311, 1982, U.S. Pat. Nos. 5,330,896 and 5,643,740), was tested in steroid-refractory acute graft-versus-host disease (Heslop et al. The Lancet 346: 805-806; Deeg et al. 2001 Blood 98:2052-8). Human equivalent mAbs binding to epitopes overlapping that of CBL1 (aka ABX-CBL), near the transmembrane domain of the ECD were also developed (US2007048305A1). Koch et al. (Internat Immunol 11(5) 777-786, 1999) mapped CD147 epitopes associated with T- and B-cell activation, reporting that only the highest affinity monoclonal antibody (MEM-M6/6) of a group of antibodies made to CD147 was effective in preventing human T-cell activation and proliferation by the mAbs against CD3, OKT3. A murine antibody to tumor cell derived human CD147, EIIF4 (Ellis, 1989 Cancer Res 49:3385-91; Biswas et al.
"Thus, while certain antibodies and other antagonists of CD147 are known, how the complex nature of the protein, including the two immunoglobulin domains, influences the myriad biological activities has not been thoroughly illucidated. Domain specific antagonists may prove to be useful therapeutic candidates for treating various of the pathologies associated with CD147 display and/or activation on various tissues. For example, therapeutic agents capable of blocking production MMPs or VEGF activity induced by CD147 could be advantageous in cancer therapy.
"Accordingly, there is a need to provide human antibodies specific for human CD147 for use in therapy to diminish or eliminate symptoms of CD147-dependent diseases, as well as improvements over known antibodies or fragments thereof."
In addition to obtaining background information on this patent, NewsRx editors also obtained the inventors' summary information for this patent: "The present invention provides anti-CD147 monoclonal antibodies capable of blocking activities associated with one or more bioactivities associated with CD147 including but not limited to angiogenesis, VEGF production, matrix metalloproteinase production (MMP-1, MMP-2, and MMP-9), and which antibody has a specific binding site on human CD147.
"One aspect of the invention is an isolated antibody reactive with human CD147 protein having the antigen binding ability of a monoclonal antibody having the amino acid sequences of the light chain complementarity determining regions (CDRs) as set forth in SEQ ID NOs: 9, 11, 13 and 15 and the amino acid sequences of the heavy chain CDRs as set forth in SEQ ID NOs: 10, 12, 14 and 16.
"Another aspect of the invention is an isolated antibody reactive with a CD147 protein epitope located at residues 65-75 of SEQ ID NO: 1 of the CD147 protein.
"Another aspect of the invention is an isolated antibody having heavy chain CDR1, CDR 2 and CDR3 (Hc-CDR1, Hc-CDR2 and Hc-CDR3) amino acid sequences selected from the sequences shown in SEQ ID NOs: 10, 12 and 14 respectively and a light chain CDR3 (Lc-CDR3) as shown in Formula (I): Gln Gln Xaa.sub.1 Tyr Ser Xaa.sub.2 Pro Xaa.sub.3Thr (I) wherein Xaa.sub.1 is Tyr or Asp; Xaa.sub.2 is Tyr or Ser; Xaa.sub.3 is Phe or Tyr or absent; and Xaa.sub.4 is Thr or Phe; and light chain CDR1 (Lc-CDR1) and light chain CDR2 (Lc-CDR2) amino acid sequences selected from the sequences as shown in SEQ ID NOs: 9 and 11, respectively.
"Another aspect of the invention is an isolated antibody having Hc-CDR1, Hc-CDR2 and Hc-CDR3 amino acid sequences shown in SEQ ID NOs: 10 and Lc-CDR1 Lc-CDR2, and Lc-CDR3 amino acid sequences as shown in SEQ ID NOs: 9.
"Another aspect of the invention is an isolated antibody having Hc-CDR1, Hc-CDR2 and Hc-CDR3 amino acid sequences shown in SEQ ID NOs: 12 and Lc-CDR1 Lc-CDR2, and Lc-CDR3 amino acid sequences as shown in SEQ ID NOs: 11.
"Another aspect of the invention is an isolated antibody having Hc-CDR1, Hc-CDR2 and Hc-CDR3 amino acid sequences shown in SEQ ID NOs: 14 and Lc-CDR1 Lc-CDR2, and Lc-CDR3 amino acid sequences as shown in SEQ ID NOs: 13.
"Another aspect of the invention is an isolated antibody having Hc-CDR1, Hc-CDR2 and Hc-CDR3 amino acid sequences shown in SEQ ID NOs: 16 and Lc-CDR1 Lc-CDR2, and Lc-CDR3 amino acid sequences as shown in SEQ ID NOs: 15.
"Another aspect of the invention is an isolated polynucleotide encoding an antibody of the invention.
"In another aspect, the invention relates to an antibody which binds to a common epitope defined by antibody 4A5 and 5F6, and/or which compete for binding to the CD147 with antibody 4A5 or 5F6 or which have other functional binding characteristics exhibited by antibody 4A5 and 5F6 such as protecting against D2-exchange at residues 65-74 of SEQ ID NO: 1. Such antibodies include, for example, those which compete with antibody 4A5 or 5F6 and bind to CD147 with a dissociation constant (K.sub.D) of 10.sup.-7 M or less, such as of 10.sup.-8 M or less, 10.sup.-9 M or less, 10.sup.-10 M or less, or even lower (e.g., 10.sup.-11 M or less).
"The present invention provides specific binding domains derived from exemplary antibody sequences capable of binding to human CD147 as defined herein and which block activities associated with one or more bioactivities associated with CD147 including but not limited to angiogenesis, VEGF production, and matrix metalloproteinase production (MMP-1, MMP-2, and/or MMP-9 production). Specific binding domains are those domains specified as the variable regions and CDR residues as specified within SEQ ID NOS: 9-16. The invention further includes antibodies derived from SEQ ID NOS: 9-16 such as humanized or reshaped antibodies or antibody binding domains that retain the ability to immunospecifically bind to human CD147 with an affinity of KD of 10.sup.-7 M or less, compete with antibody 2H3, 4A5, or 5F6 for binding to CD147, and block the bioactivities of CD147.
"Thus, one aspect of the invention relates to a humanized antibody comprising a humanized heavy chain and humanized light chain, wherein: (1) the humanized heavy chain variable region comprise three complementarity determining regions (CDRS) from the mouse 2H3, 4A5, 5F6 or 2C8 heavy chain and a framework from a human acceptor antibody heavy chain, optionally having one or more human framework residue substitutions, and (2) the humanized light chain variable region comprises three complementarity determining regions from the mouse 2H3, 4A5, 5F6 or 2C8 light chain and a framework from a human acceptor antibody light chain optionally having one or more human framework residue substitutions; and the humanized antibody specifically binds to human CD147.
"In a further embodiment, the humanized antibody may be composed of one or more CDRs that are further engineered with one or more substitutions or deletions, for example, those that are 90%, 95%, 98% or 99.5% identical to one or more CDRs of 2H3, 4A5, 5F6 or 2C8.
"Another embodiment relates to the treatment or prevention of pathological conditions associated with CD147 bioactivity by administering a therapeutically or prophylactically effective amount of one antibody of the present invention or a mixture of antibodies of the present invention to a subject in need of such treatment.
"In a further embodiment, there are provided antigen epitopes as a component of a vaccine. The epitopes described above comprising SEQ ID NO: 1 residues 65-74 or conservative changes thereof which are still recognized by the antibodies of the invention, are useful for actively immunizing a host to elicit production of antibodies against CD147 capable of the combating or preventing pathological conditions associated with CD147 bioactivity."
For more information, see this patent: Cunningham, Mark; Swencki-Underwood,
Keywords for this news article include: Antibodies, Oncology, Treatment, Immunology, Proteomics, Amino Acids, Angiogenesis, Therapeutics, Blood Proteins, Immunoproteins, Cancer Vaccines, Immunoglobulins, Serum Globulins, Peptide Hydrolases, Enzymes and Coenzymes, Metalloendopeptidases, Matrix Metalloproteinases,
Our reports deliver fact-based news of research and discoveries from around the world. Copyright 2014, NewsRx LLC
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