The present invention encompasses monoclonal antibodies that bind to lipoteichoic acid (LTA) of Gram positive bacteria. The antibodies also bind to whole bacteria and enhance phagocytosis and killing of the bacteria in vitro. The invention also provides antibodies having human sequences (chimeric, humanized and human antibodies). The invention also sets forth the variable regions of three antibodies within the invention and presents the striking homology between them.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention encompasses broadly reactive, opsonic, and protective monoclonal and chimeric antibodies that bind to lipoteichoic acid (LTA) of Gram positive bacteria. The antibodies also bind to whole bacteria and enhance phagocytosis and killing of the bacteria in vitro and enhance protection from lethal infection in vivo. The present invention further encompasses opsonic antibodies to LTA that share a high degree of sequence homology. The present invention also encompasses antibodies having variable regions derived from two or more different anti-LTA antibodies.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides murine antibodies, including monoclonal antibodies, and chimeric, humanized and fully human antibodies, fragments, derivatives, and regions thereof, which bind to lipoteichoic acid (LTA) of Gram positive staphylococci. Gram positive bacteria, unlike Gram negative bacteria, take up the Gram stain as a result of a difference in the structure of the cell wall. The cell walls of Gram negative bacteria are made up of a unique outer membrane of two opposing phospholipid-protein leaflets, with an ordinary phospholipid in the inner leaflet but the extremely toxic lipopolysaccharide in the outer leaflet. The cell walls of Gram positive bacteria seem much simpler in comparison, containing two major components, peptidoglycan and teichoic acids plus additional carbohydrates and proteins depending on the species.

Moreover, because the basis of the binding to Gram positive bacteria is the presence of LTA and because LTA is a major component of the cell walls of Gram positive bacteria and is highly conserved, the antibodies of the claimed invention are broadly reactive against Gram positive bacteria. This broad reactivity permits the antibodies of the invention to block the binding of Gram positive bacteria to epithelial cells, such as human epithelial cells (50-54). Finally, these antibodies exhibit broad opsonic activity and consequently enhance phagocytosis and killing of Gram positive bacteria. Accordingly, the invention provides broadly reactive, opsonic, and protective antibodies for the diagnosis, prevention, and/or treatment of bacterial infections caused by Gram positive bacteria.

Among the Gram positive Staphylococci against which the antibodies of the invention are directed are S. aureus (a coagulase positive bacteria) and S. epidermidis (a coagulase negative bacteria).

Three of the monoclonal antibodies of the invention (M110, M120, and MAb-391.4) bind strongly to LTA. M110 and M120 also exhibit high opsonic activity for S. epidermidis, while MAb-391.4 is also opsonic for S. epidermidis, but less so. M120 is also highly opsonic against S. aureus. M110 was derived from mice immunized with whole S. epidermidis strain Hay as described in detail in U.S. Pat. No. 6,610,293, which is incorporated herein by reference. In screening for hybridomas, the antibodies of one clone (hybridoma line 96-105CE11 IF6, which produces antibody M110) were found to bind very strongly to Gram positive bacteria such as strain Hay, all three serotypes of S. epidermidis, S. hemolyticus, S. hominus, and two serotypes of S. aureus, but not to the Gram negative control, Haemophilus influenza (see U.S. Pat. No. 6,610,293).

M120 was derived from mice immunized with conjugates of S. aureus LTA. The antibodies of one clone (00-107GG12 ID 12, which produces antibody M120) were found to bind strongly to LTA, and were opsonic for S. aureus type 5 and S. epidermidis strain Hay.

MAb-391.4 is from QED Biosciences, and was derived from mice immunized with whole UV-killed S. aureus.

The variable regions of M110, M120, and 391.4 were sequenced and compared, revealing a surprising 88% identity (203/230) at the amino acid level. Further, the level of identity was found to be 96% (220/230) between the antibodies that are highly opsonic for S. epidermidis, M110 and M120. We believe that this level of homology between three monoclonal antibodies that were raised in three different mice, using three different antigen preparations from two different types of bacteria, is unprecedented. To understand how unexpected this finding is, one need only consider how vast and diverse is the collection of antibodies in the immune system.

The immune system is made up of a large number of B cells, each bearing antibodies of a different specificity, but only about 1 in 10,000 to 1 in 1,000,000 B cells is specific for a particular antigen. When a foreign antigen, such as is found on the surface of a bacteria, enters the blood stream, the appropriate B cell recognizes that antigen and then enters a lymph node where it undergoes rapid division to produce many progeny bearing the identical specificity. However, the rapidly dividing B cells also undergo somatic hypermutation. Somatic hypermutation results in about half of the B cells acquiring mutations in their rearranged heavy and light chain genes, with mutation occurring preferentially in complementarity determining regions (CDRs) of the variable regions. Mutated B cells that retain their ability to bind antigen continue to secrete antibody, while those that no longer bind antigen undergo apoptosis. As the antigen is cleared from the host, only B cells that have very high antigen affinity survive in a process called affinity maturation. The surviving activated B cells differentiate into plasma cells, which are short-lived and secrete antibody, and memory B cells, which are long-lived lymphocytes bearing membrane-bound antibody that can be rapidly stimulated when the antigen is re-introduced.

The processes of somatic hypermutation and affinity maturation result in progeny B cells that are of higher affinity and have immunoglobulins of different amino acid sequence than the original activated B cell. Therefore, a single B cell that is activated by a foreign antigen can produce many progeny of differing affinity and immunoglobulin amino acid sequence.

Because of these processes, it is generally believed that two animals immunized with the same antigen will produce vastly different antibody repertoires. Nickerson and colleagues demonstrated this concept when they showed that a mouse monoclonal antibody and a human monoclonal antibody that showed nearly identical binding to the same blood group A antigen shared only 15% and 37% identity in their heavy and light chain CDRs (55). X-ray crystallography studies of two antibodies that both bind to hemagglutinin of influenza virus, reveal that, although they share only 56% sequence identity, they both bind with similar affinities and in the same orientation to the same epitope (56).

It has been postulated that the immune system has evolved to provide a maximum range of antigen specificities and redundancy, rather than to bind to specific antigens (55). It follows, therefore, that antibodies derived from the same mouse may be of high specificity, but low homology, because any number of progenitor B cells may be specific for the immunized antigen. Amplification and somatic mutation of those progenitors may, however, result in groups of antibodies that are of higher homology within the group, although they are of very low homology between groups. Antibodies raised against the same immunogen in two or more different mice will necessarily be even less homologous, because they do not share progenitor B cells.

Three specific antibodies of the present invention, M110, M120, and MAb-391.4, were not only raised in different mice, but with different immunogens: M110 was raised to whole S. epidermidis, M120 was raised to purified and conjugated S. aureus LTA, and MAb-391.4 was raised to whole UV-killed S. aureus. Yet, though these antibodies were raised against different immunogen preparations in different mice, they share 88% identity at the amino acid level in both the heavy and light chain variable regions. This high degree of homology suggests that LTA contains a highly antigenic, and highly conserved, epitope which is bound by the three antibodies in a very similar manner. This epitope and mode of binding may be responsible for the high opsonic activity of the monoclonal antibodies.

MAb-391.4 and human/mouse chimeric antibodies of M110 and M120, designated A110 and A120, respectively, were tested for opsonic activity. MAb-391.4, A110, and A120 each demonstrated a high level of opsonic activity against S. epidermidis strain Hay. (see also U.S. Pat. No. 6,610,293).

MAb A110 is currently being manufactured under GMP conditions in preparation for clinical trials. Additional disclosure regarding the MAb A110 is provided in U.S. Provisional Application Ser. No. 60/341,806, now expired, and in related application Methods for Blocking or Alleviating Staphylococcal Nasal Colonizaton by Intranasal Application of Monoclonal Antibodies, filed concurrently herewith, both of which are expressly incorporated by reference.

Thus, one aspect of the invention relates to antibodies that bind to the LTA of Gram positive bacteria, including both coagulase negative (S. epidermidis) and coagulase positive (S. aureus) bacteria, and that enhance the opsonization of such bacteria. These anti-LTA antibodies include monoclonal antibodies, such as M110, M120, and MAb-391.4, chimeric monoclonal antibodies A110, A120, A120a, and A120b, and other monoclonal antibodies including, chimeric, humanized, fully human antibodies, antibody fragments, and modified antibodies.

In a one aspect of the invention, as noted above, the antibody is a chimeric mouse/human antibody made up of regions from the anti-LTA antibodies of the invention together with regions of human antibodies. Chimeric or other monoclonal antibodies are advantageous in that they avoid the development of anti-murine antibodies. In at least one study, patients administered murine anti-TNF (tumor necrosis factor) monoclonal antibodies developed anti-murine antibody responses to the administered antibody (5). This type of immune response to the treatment regimen, commonly referred to as the human anti-mouse antibody response, or the HAMA response, decreases the effectiveness of the treatment and may even render the treatment completely ineffective. Humanized or chimeric human/mouse monoclonal antibodies have been shown to significantly decrease the HAMA response and to increase the therapeutic effectiveness (19).

Thus, in one aspect of the invention, a chimeric heavy chain can comprise the antigen binding region of the heavy chain variable region of the anti-LTA antibody of the invention linked to at least a portion of a human heavy chain IgG, IgA, IgM, or IgD constant region. This humanized or chimeric heavy chain may be combined with a chimeric light chain that comprises the antigen binding region of the light chain variable region of the anti-LTA antibody linked to at least a portion of the human light chain kappa or lambda constant region. Exemplary embodiments include, but are not limited to, an antibody having a mouse heavy chain variable region fused to a human 1gG.sub.1 constant region, and a mouse light chain variable region fused to a human kappa light chain constant region.

The chimeric antibodies and other MAb's of the invention may be monovalent, divalent, or polyvalent immunoglobulins. For example, a monovalent chimeric antibody is a dimer (HL) formed by a chimeric H chain associated through disulfide bridges with a chimeric L chain, as noted above. A divalent chimeric antibody is a tetramer (H2 L.sub.2) formed by two HL dimers associated through at least one disulfide bridge. A polyvalent or multivalent chimeric antibody may be based on an aggregation of chains, with or without a carrier or scaffold.

The MAbs of the invention include antibodies that contain heavy and light chain variable regions derived from two different antibodies. In one embodiment, the heavy and light chain variable regions are derived from two antibodies that bind to the same molecule, e.g. LTA. Exemplary embodiments include A120a, which is a human/mouse chimeric antibody that has a heavy chain variable region from A110 and a light chain variable region from A120; and A120b, which is a human/mouse chimeric antibody that has a heavy chain variable region from A120 and a light chain variable region from A110. Additional exemplary embodiments include antibodies that comprise a heavy chain variable region from MAb-391.4, and a light chain variable region from either of A110 or A120, and antibodies that comprise a light chain variable region from MAb-391.4, and a heavy chain variable region from either of A110 or A120.

In yet another aspect, the invention is a collection of opsonic monoclonal antibodies that bind to LTA and that exhibit a high degree of homology in the variable regions at either the amino acid or nucleic acid level, or both. In one embodiment, this collection comprises one or more of M110, M120, their human/mouse chimeric counterparts, A110, A120, and MAb-391.4. In one aspect, the amino acid sequences of the variable regions are at least 75% identical, at least 80% identical, at least 85% identical, at least 88% identical, at least 90% identical, or at least 95% identical as defined above.

In addition to the antibodies, the present invention also encompasses the DNA sequences of the genes coding for the antibodies (see, e.g., FIGS. 5, 6, and 9 (see Original Patent); SEQ ID NOs: 11, 13-15, 19, and 20) as well as the polypeptides encoded by the DNA (see, e.g., FIGS. 5, 6, and 10; SEQ ID NOs: 10, 12, 16, 17, 21, and 22). Those figures provide the variable regions of the heavy and light chains of A110, A120, and MAb-391.4, including the complementarity determining regions (CDRs), the hypervariable amino acid sequences within antibody variable regions that usually interact with the antigen. As noted above, the DNA and amino acid sequence homology between A110 and A120 is striking. There is a 94% homology (216/229) at the amino acid level and a 96% homology (662/687) at the DNA level between the antibodies. This suggests that these antibodies share a sequence and structural similarity.

The invention includes peptide sequences for, and DNA sequences encoding, full-length antibodies and portions thereof, as well as CDRs and FRs relating to these MAbs. The invention further includes DNA and peptide sequences that are homologous to these sequences. In one embodiment, these homologous DNAs and peptide sequences are about 70% identical, although other embodiments include sequences that are about 75%, 80%, 85%, 88%, 90%, and 95% or more identical. As indicated above, determining levels of identity for both the DNA and peptide sequence is well within the routine skill of those in the art.

As shown in FIG. 10A (see Original Patent), alignment of the A110, A120, and 391.4 light chain variable regions (Seq. ID Nos. 16, 10, and 21, respectively) shows identical amino acids in 95 of 106 amino acids, or more than 89% identity overall. Within the region spanning the CDRs (amino acids 24 to 96 of the light chain variable regions) the percent identity is about 93% (68 out of 73 amino acids). It is predicted that light chain variable regions with a somewhat lower overall identity would still form MAbs that specifically bind LTA, and are therefore within the scope of the invention. The CDRs themselves show at least 88% identity, in particular, CDR1 (amino acids 24-33), CDR2 (amino acids 49-55), and CDR3 (amino acids 88-96), show 9/10, 7/7, and 8/9 identical amino acids. Likewise, the framework regions (FRs) surrounding the CDRs are also highly conserved: amino acids 1-23 of SEQ ID Nos. 16, 10, and 21 show greater than 86% identity (20/23 matching amino acids); amino acids 34-48 show about 93% identity (14/15); amino acids 56-87 show about 93% identity (68/73); and amino acids 97-106 show 70% identity.

Similarly, in FIG. 10B (see Original Patent), alignment of the A110, A120, and 391.4 heavy chain variable regions (Seq. ID Nos. 17, 12, and 22, respectively) also shows a high degree of sequence identity. Counting single amino acid gaps and insertions as single-point mismatches, Seq. ID Nos. 17, 12, and 22 show 86% identity overall (108/125 identical amino acids). It is predicted that heavy chain variable regions with a somewhat lower overall identity would still form MAbs that specifically bind LTA, and are therefore within the scope of the invention. The degree of identity is particularly high in the FR region preceding CDR1 through the FR region preceding CDR3, in particular, the 96 base region from amino acid 16 to 101 of Seq. ID Nos. 17, 12, and 22 shows 8 mismatches or approximately 91% identity. CDR1, itself, shows 90% identity over 10 amino acids (amino acids 26-35), and CDR2 (amino acids 50-69) shows about 89% identity over 19 amino acids. The framework regions surrounding the CDRs are also highly conserved. Amino acids 1-25 of SEQ ID Nos. 17, 12, and 22 show 92% identity (23/25 matching amino acids); amino acids 36-49 show 100% identity over 14 amino acids; the FR region between CDR2 and CDR3 (amino acids 70 to about 101) shows about 87% identity (over 31-32 amino acids); and amino acids 115-125 show 90% identity.

Thus, in one aspect, the invention encompasses polypeptides (including regions of larger polypeptides, such as MAbs) that 1) exhibit high sequence homology to Seq. ID Nos. 10, 12, 16, 17, 21, or 22, or defined regions thereof, and 2) are capable of functioning as all or part of the variable region of a MAb that specifically binds LTA. In one embodiment, such polypeptides comprise, or are at least 70%, 75%, 77% 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 95% identical to, any of Seq. ID Nos. 10, 12, 16, 17, 21, or 22. Conversely, polypeptides within the scope of the invention may be less than 100%, 99%, 95%, 90%, 80% or less identical to Seq. ID Nos. 10, 12, 16, 17, 21, or 22 provided that they are capable of functioning as all or part of the variable region of a MAb that specifically binds to LTA.

In another embodiment, polypeptides within the scope of the invention comprise, or are at least 70%, 75%, 77%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 95% identical to, amino acids 24 to 96 of any of Seq. ID Nos. 10, 16, or 21. In another embodiment, such polypeptides comprise, or are at least 70%, 75%, 77%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 95% identical to, 1) amino acids 24-33, 49-55, and 88-73 of Seq. ID Nos. 10, 16, or 21, or 2) amino acids 26-35 or 50-69 of Seq. ID Nos. 12, 17, or 22; and are capable of functioning as a CDR, or portion thereof, in a MAb that specifically binds to LTA. In another embodiment, such polypeptides comprise, or are at least 70%, 75%, 77%, 80%, 81%, 82%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 93%, 95% identical to, 1) amino acids 1-23, 34-48, 56-87, and 97-106 of Seq. ID Nos. 10, 12, 16, 17, 21, or 22, or 2) amino acids 1-25, 36-49, 70-101, or 115-125 of Seq. ID Nos. 12, 17, or 22; and are capable of functioning as a framework region, or portion thereof, in a MAb that specifically binds to LTA.

The invention further comprises collections of a multiplicity of any of the above sequences capable of functioning as all or part of the variable region of a MAb that specifically binds to LTA, as part of a larger polypeptide, MAb, collection of MAbs or aggregation of MAbs; and the use thereof in prophylaxis, treatment, and for the production of pharmaceutical compounds or medicaments. The invention further comprises any non-naturally occurring RNA, DNA, or vector thereof, encoding any of the above sequences capable of functioning as all or part of the variable region of a MAb that specifically binds to LTA, as well as plasmids, viruses, bacteria, yeast, microorganisms, cell lines, transgenic plants or animals harboring or expressing such nucleic acids. Thus, the invention contemplates production systems for Mabs, light chains, heavy chains, and portions thereof, comprising 1) a cell (including bacteria, yeast, microorganisms, eukaryotic cell lines, transgenic plant or animal) in connection with 2) at least one recombinant nucleic acid capable of directing the expression of any of the Mabs or related polypeptides of the invention.

The invention thus further comprises a general method of identifying highly antigenic and highly conserved epitopes by raising antibodies against different immunogen preparations in different mice, sequencing the variable regions of the antibodies, comparing the variable regions, and identifying antibodies that share a high degree of homology in the variable regions.

The DNA sequences of the invention can be identified, isolated, cloned, and transferred to a prokaryotic or eukaryotic cell for expression by procedures well-known in the art. Such procedures are generally described in Molecular Cloning: A Laboratory Manual, as well as Current Protocols in Molecular Biology (44, 45), which are incorporated by reference. Guidance relating more specifically to the manipulation of sequences of the invention may be found in Antibody Engineering, and Antibodies: A Laboratory Manual (64, 65), both of which are incorporated by reference in their entirety. In certain embodiments, a CDR can be grafted onto any human antibody framework region using techniques standard in the art, in such a manner that the CDR maintains the same binding specificity as in the intact antibody. As noted as above, an antibody that has its CDRs grafted onto a human framework region is said to be "humanized". Humanized, and fully human antibodies generally also include human constant regions, thus maximizing the percentage of the antibody that is human-derived, and potentially minimizing the HAMA response.

In addition, the DNA and peptide sequences of the antibodies of the invention, including both monoclonal and chimeric antibodies, humanized and fully human antibodies, may form the basis of antibody "derivatives," which include, for example, the proteins or peptides encoded by truncated or modified genes. Such proteins or peptides may function similarly to the antibodies of the invention. Other modifications, such as the addition of other sequences that may enhance the effector function, which includes phagocytosis and/or killing of the bacteria, are also within the present invention.

The present invention also discloses a pharmaceutical composition comprising the antibodies, whether monoclonal or chimeric, humanized, or fully human, together with a pharmaceutically acceptable carrier. The pharmaceutical compositions of the invention may alternatively comprise the isolated antigen, epitope, or portions thereof, together with a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers can be sterile liquids, such as water, oils, including petroleum oil, animal oil, vegetable oil, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Saline solutions, aqueous dextrose, and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, 18th Edition (13), which is herein incorporated by reference.

Additionally, the invention may be practiced with various delivery vehicles and/or carriers. Such vehicles may increase the half-life of the MAbs in storage and upon administration including, but not limited to, application to skin, wounds, eyes, lungs, or mucus membranes of the nasal or gastrointestinal tract, or upon inhalation or instillation into the nares. These carriers comprise natural polymers, semi-synthetic polymers, synthetic polymers, lipososmes, and semi-solid dosage forms (21, 29, 33, 35, 36, 46). Natural polymers include, for example, proteins and polysaccharides. Semi-synthetic polymers are modified natural polymers such as chitosan, which is the deacetylated form of the natural polysaccharide, chitin. Synthetic polymers include, for example, polyphosphoesters, polyethylene glycol, poly (lactic acid), polystyrene sulfonate, and poly (lactide coglycolide). Semi-solid dosage forms include, for example, dendrimers, creams, ointments, gels, and lotions. These carriers can also be used to microencapsulate the MAbs or be covalently linked to the MAbs.

Finally, the present invention provides methods for treating a patient infected with, or suspected of being infected with, a Gram-positive bacteria such as a staphylococcal organism. The method comprises administering a therapeutically effective amount of a pharmaceutical composition comprising the anti-LTA immunoglobulin (whether monoclonal, chimeric, humanized, or fully human, including fragments, regions, and derivatives thereof) and a pharmaceutically acceptable carrier. A patient can be any human or non-human mammal in need of prophylaxis or other treatment. Representative patients include any mammal subject to S. aureus or other staphylococcal or Gram-positive infection or carriage, including humans and non-human animals such as mice, rats, rabbits, dogs, cats, pigs, sheep, goats, horses, primates, ruminants including beef and milk cattle, buffalo, camels, as well as fur-bearing animals, herd animals, laboratory, zoo, and farm animals, kenneled and stabled animals, domestic pets, and veterinary animals.

A therapeutically effective amount is an amount reasonably believed to provide some measure of relief, assistance, prophylaxis, or preventative effect in the treatment of the infection. A therapeutically effective amount may be an amount believed to be sufficient to block a bacterial infection. Similarly, a therapeutically effective amount may be an amount believed to be sufficient to alleviate a bacterial infection. Such therapy as above or as described below may be primary or supplemental to additional treatment, such as antibiotic therapy, for a staphylococcal infection, an infection caused by a different agent, or an unrelated disease. Indeed, combination therapy with other antibodies is expressly contemplated within the invention.

A further embodiment of the present invention is a method of preventing such infections, comprising administering a prophylactically effective amount of a pharmaceutical composition comprising the anti-LTA antibody (whether monoclonal, chimeric, humanized, or fully human) and a pharmaceutically acceptable carrier.

A prophylactically effective amount is an amount reasonably believed to provide some measure of prevention of infection by Gram positive bacteria. Such therapy as above or as described below may be primary or supplemental to additional treatment, such as antibiotic therapy, for a staphylococcal infection, an infection caused by a different agent, or an unrelated disease. Indeed, combination therapy with other antibodies is expressly contemplated within the invention.

The antibodies and the pharmaceutical compositions of the invention may be administered by intravenous, intraperitoneal, intracorporeal injection, intra-articular, intraventricular, intrathecal, intramuscular or subcutaneous injection, or intranasally, dermally, intradermally, intravaginally, orally, or by any other effective method of administration. The composition may also be given locally, such as by injection to the particular area infected, either intramuscularly or subcutaneously. Administration can comprise administering the pharmaceutical composition by swabbing, immersing, soaking, or wiping directly to a patient. The treatment can also be applied to objects to be placed within a patient, such as dwelling catheters, cardiac valves, cerebrospinal fluid shunts, joint prostheses, other implants into the body, or any other objects, instruments, or appliances at risk of becoming infected with a Gram positive bacteria, or at risk of introducing such an infection into a patient.

As a particularly valuable corollary of treatment with the compositions of the invention (pharmaceutical compositions comprising anti-LTA antibodies, whether, monoclonal, chimeric, humanized or fully human) may be the reduction in cytokine release that results from the introduction of the LTA of a Gram positive bacteria (49). As is now recognized in the art, LTA induces cytokines, including, for example, tumor necrosis factor alpha, interleukin 6, and interferon gamma (see, e.g., (37)). Accordingly, the compositions of the invention may enhance protection at three levels: (1) by binding to LTA on the bacteria and thereby blocking the initial binding to epithelial cells and preventing subsequent invasion of the bacteria; (2) by binding to LTA on bacteria and thereby enhancing opsonization of the bacteria and clearance of the bacteria from tissues and/or blood; and/or (3) by binding to LTA and partially or fully blocking cytokine release and modulating the inflammatory responses to prevent shock and tissue destruction.

Having generally described the invention, it is clear that the invention overcomes some of the potentially serious problems described in the Background section regarding the development of antibiotic resistant Gram positive bacteria. As set forth above, Staphylococci and Streptococci (such as S. faecalis) have become increasingly resistant to antibiotics and, with the recent spread of vancomycin resistant strains, antibiotic therapy may become totally ineffective

Claim 1 of 31 Claims

1. An isolated nucleic acid molecule comprising a nucleotide sequence encoding a monoclonal antibody light chain, or variable region thereof, the light chain or variable region comprising the sequence as set forth in residues 1-106 of SEQ ID NO:10.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.