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Immunotherapy of b cell malignancies and autoimmune diseases using unconjugated antibodies and conjugated antibodies and antibody combinations and fusion proteins

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Immunotherapy of b cell malignancies and autoimmune diseases using unconjugated antibodies and conjugated antibodies and antibody combinations and fusion proteins


The invention is directed to a method for treating a treating and diagnosing a B cell-related disease, T cell-related disease or an autoimmune disease in a mammal by concurrently or sequentially administering to the mammal a therapeutic composition that comprises a pharmaceutically acceptable vehicle and at least one conjugated antibody, wherein predosing with a non-radiolabeled antibody is not performed.
Related Terms: Antibodies Antibody Autoimmune Autoimmune Diseases Autoimmune Disease Fusion Immunotherapy Mammal Proteins Concurrent Diseases Immune Disease Immune Diseases

Browse recent Immunomedics, Inc. patents - Morris Plains, NJ, US
USPTO Applicaton #: #20140147382 - Class: 424 149 (USPTO) -
Drug, Bio-affecting And Body Treating Compositions > Radionuclide Or Intended Radionuclide Containing; Adjuvant Or Carrier Compositions; Intermediate Or Preparatory Compositions >Attached To Antibody Or Antibody Fragment Or Immunoglobulin; Derivative

Inventors: David M. Goldenberg, Hans Hansen

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The Patent Description & Claims data below is from USPTO Patent Application 20140147382, Immunotherapy of b cell malignancies and autoimmune diseases using unconjugated antibodies and conjugated antibodies and antibody combinations and fusion proteins.

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CROSS-REFERENCE TO RELATED APPLICATIONS

This application is based on U.S. provisional patent application Ser. No. 60/437,145, filed Dec. 31, 2002. The entire contents of this application, including its specification, claims and drawings, are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to immunotherapeutic method for treating B-cell related malignancies, particularly aggressive non-Hodgkin\'s lymphomas. In particular, this invention is directed to methods for treating and diagnosing a B cell-related disease, T cell-related disease or an autoimmune disease in a mammal by administering to the mammal a therapeutic composition, wherein predosing with a non-radiolabeled antibody is not performed.

BACKGROUND OF THE INVENTION

B-cell lymphomas express surface antigens that have shown to be good targets for therapy with monoclonal antibodies (Mab). Antibodies, either used alone (naked antibodies) or in conjunction with chemotherapy, can be conjugated with toxins or with radionuclides for radioimmunotherapy (RAIT). The radiolabelled antibody is administered after (Kaminski, M. S. et al., J. Clin. Oncol. 19:3918-3928, 2001) or together (Press, O. W. et al, New Engl. J. Med. 329:1219-24, 1993) with unlabelled antibody to improve dose distribution. Most investigators use a radiolabeled mouse antibody combined with an unlabeled antibody, which is murine or chimeric. It has been considered advantageous to radiolabel a mouse antibody from a toxicological point of view due to its shorter half-life compared to a chimeric antibody. A Mab with longer half-life gives a longer residence time of the radioimmunoconjugate in blood and bone marrow and probably thus induces more toxicity. Since the antibody in its own right hardly induces toxicity both mouse and chimeric unlabelled antibodies are used to improve dose distribution by allegedly saturating antigen on normal cells and tissues in the body (cf. Kaminski, U.S. Pat. No. 5,595,721; Wiseman et al., Crit. Rev. Oncol. Hematol. 39:181-194, 2001).

The use of monoclonal antibodies in targeted radiotherapy of cancers (radioimmunotherapy; RAIT) has produced striking clinical responses in hematologic diseases such as non-Hodgkin\'s lymphoma (NHL). New strategies are presently examined in an effort to minimize the systemic toxicity of a circulating radionuclide and the sensitization of tumors by radiation. The former being carried out by pretargeting and the latter by combination therapy with radiosenzitizing drugs. See Govindan, S. V et al., Current Trends, Pharmaceutical Science and Technology Today 3:90-98, 2000.

The anti-tumor activity of RAIT is mainly due to the associated radioactivity of the radiolabel attached to the antibody, which emits continuous, exponentially decreasing low-dose-rate irradiation with a heterogeneous dose deposition. Four radiolabeled antibody products are progressing towards commercialization for the RAIT of NHL. They include 131I-tositumomab (Bexxar™), 90Y-ibritumomab tiuxetan (Zevalin™), 90Y-epratuzumab (hLL2) and 131I-Lym-1. For a more detail review of these products, see Goldenberg, D. M., Critical Reviews in Oncology/Hematology 39:195-201, 2001, and Goldenberg, D. M., J. Nucl. Med. 43:693-713, 2002.

Bexxar (Corixa Corp., Seattle, Wash.) and Zevalin (IDEC-Y2B8; IDEC Pharmaceuticals, San Diego, Calif.) are both murine monoclonal antibodies (Mabs) directed against CD20 antigen expressed in the surface of normal and malignant B-lymphocytes. Bexxar is used as an IgG2a murine Mab with cold murine antibody added, whereas Zevalin has the murine antibody labeled and cold human.mouse chimeric rituximab (Rituxan™, IDEC-Genentech) added to the product. Both products provide for pretherapy cold antibody dosing in order to improve tumor targeting, which involves a 1-h infusion of 450 mg of unlabeled Bexxar antibody and a 4-6 h infusion of 450 mg of rituximab with Zevalin. Both products have shown a higher and more durable responses than naked antibodies, however, they also have dose-limiting toxicity, predominantly myelotoxicity. Zevalin was approved by the Food and Drug Administration (FDA) for the treatment of recurrent low grade or transformed B cell non-Hodgkin\'s lymphoma. These radiolabeled anti-CD-20 Mab must be preceded by a dose of cold antibodies to enable good tumor localization. In fact, the specific localization numbers for mindium -Zevalin drop from 78% to 15% tumor uptake at specific tumor sites when predosing is involved (Wiseman et al., ibid).

Epratuzumab (90Y -epratuzumab) is a humanized IgG1 antibody directed against the anti-CD22 antigen. The antigen is fast internalized upon antibody binding. The naked antibody has been reported to show efficacy in follicular as well as diffuse large B-cell lymphoma (Leonard, J. P. et al., Epratuzumab (hLL2, anti-CD22 humanized monoclonal antibody) is an active and well-tolerated therapy for refractory/relapsed diffuse large B-cell non-Hodgkin\'s lymphoma (NHL). Blood (Suppl) 96:578a [abstr. 2482], 2000; Press, O. W. et al., Immunotherapy of Non-Hodgkin\'s Lymphomas. Hematology (Am. Soc. Hematol. Educ. Program), p. 221-40, 2001). Epratuzumab is not expected to give rise to human anti-human antibodies (HAHA), which makes it suited for repeated dosing. The mouse parental antibody, mLL2,labelled with 131I and has shown efficacy in various subtypes of B-cell lymphoma (Linden, O. et al. Clin. Cancer Res. 5:3287s-3291s, 1999). After internalization, the 131I-labelled antibody is dehalogenated and the radionuclide is released from the cell. Radiometals like yttrium are retained in the cell upon internalization (Sharkey, R. M., et al. Cancer Immunol. Immunother. 44:179-88, 1997). The shorter physical half-life of 90Y compensates in some degree for the longer half-life of epratuzumab and provides the rational for their combination.

RAIT is usually given as a single infusion. There are, however, theoretical advantages of a fractionated approach, since fractionation would better deal with the problem of heterogeneity in absorbed dose, as outlined in O\'Donoghue, J. A., Dosimetric Principles of Targeted Radiotherapy, in Radioimmunotherapy of Cancer, A. R. Fritzberg (ed.), Marcel Dekker, Inc., p. 1-20, New York, Basel, 2000. There are also experimental data supporting that therapeutic response can be improved by splitting a large single administration of radiolabelled antibody into a number of smaller administrations (Schlom, J. et al. J. Natl. Cancer Inst. 82:763-71, 1990). Approaches with two infusions as well as multiple have been explored clinically using mouse antibodies (DeNardo, G. L., et al. Cancer Biother. Radiopharm. 13:239-54, 1998; Vose, J. M., et al . J Clin. Oncol. 18:1316-23, 2000).

Intratumoral variability in the expression of CD22 antigen has been reported. In fresh tumor samples from five patients, 52-89% of lymphoma cells were found to bear the antigen for the anti-CD22 MAb HD6 (Press, O. W. et al. Cancer Res. 49:4906-12, 1989). One alleged advantage of RAIT using long range β-emitters is their ability to kill antigen negative tumour cells in the vicinity of the targeted cells. By assessing the antigen expression of tumour cells before therapy, one could study the clinical relevance of this concept in the setting of RAIT using the anti-CD22 90Y-labelled epratuzumab.

Research was undertaken to confirm the theoretical advantages of dose fractionation and the published experimental data that support it. The study was intended to investigate the feasibility of fractionated RAIT, using a radiolabeled humanized antibody. It was found that after predosing with 100 mg of the humanized CD22 Mab, epratuzumab, labelled with 111In for dosimetry purposes, subsequent fractionated doses of 90Y-labelled epratuzumab at doses of up to 7.5 mCi/m2, once weekly for up to 2-3 weeks, resulted in tolerable and effective radioimmunotherapy (Linden et al., Cancer Biother Radiopharm 2002; 17: 490 [abstract 47]. Although these clinical studies suggest that fractionated therapy of a radioimmunoconjugate is feasible, no comparison was made with administered a single high-dose of the radioimmunoconjugate in terms of safety and efficacy. Since the first “dosimetry” dose with 111In contained 100 mg of antibody, and each susccessive injection also contained this naked antibody dose, it also could not be determined if these doses that totalled at least 300 mg of epratuzumab also served as a predosing effect as suggested in other cited studies involving CD20 antibodies. Therefore, it was not interpretable from these studies whether or not any predosing was needed for such radioimmunotherapy, particularly with CD22 antibodies.

We have now found that predosing is not used in this invention, contrary to other published studies and Kaminski\'s U.S. Pat. No. 5,595,721, to saturate the antigenic sites in the normal tissues and spleen, as practiced in the prior art. Clearly, the invention disclosed herein shows that there is a lack of a need of high antibody predosing, as practiced in the prior art.

SUMMARY

OF THE INVENTION

Accordingly, it is an object of the present invention to provide methods for treating a disease in a mammal by administering a therapeutic composition wherein predosing with a non-radiolabeled antibody, fragment or fusion protein is not performed.

It is also an object of the current invention to make the above-mentioned methods not only simple and easy for administration, yet by themselves, remain therapeutically active and have similar response rates without having a higher dose of naked antibody affecting the tumor.

It is further an object of the invention to provide methods that show a more effective response in treating aggressive non-Hodgkin\'s lymphoma, in contrast to what is demonstrated by the prior art that only shows effects in indolent forms of lymphoma.

These and other objects are achieved, in accordance with an embodiment of the present invention, by provision of a method for treating a disease in a mammal comprising concurrently or sequentially administering to the mammal a therapeutic composition that comprises a pharmaceutically acceptable vehicle and at least one conjugated antibody or a fragment thereof or a conjugated antibody fusion protein or a fragment thereof, wherein predosing with a non-radiolabeled antibody, fragment or fusion protein is not performed. The unconjugated antibody, fragment or fusion protein is optionally added with the conjugated antibody, fragment or fusion protein, as a maintenance therapy to keep tumor cells from target escape.

In a preferred embodiment, the present invention is directed to a method for treating diseases such as B-cell-related malignancies. In addition, it is also useful for treating autoimmune diseases, as well as T-cell-related malignancies.

In another preferred embodiment, the conjugated and unconjugated antibodies, fragments, and fusion proteins of the present invention can be targeted against an antigen selected from the group consisting of CD3, CD4, CD5, CD8, CD11c, CD14, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD33, CD37, CD38, CD40, CD40L, CD52, CD54, CD74, CD80, CD126, Ia, HMI.24, HLA-DR, tenascin, MUC1 and B-cell-tumor-associated antigens, including vascular endothelial antigens, such as vascular endothelial growth factor (VEGF) and placenta growth factor (P1GF). In a related vein, the conjugated and/or unconjugated antibodies, fragments or fusion proteins of the present invention can be the same or different. In addition, these antibodies can be human, murine, chimeric, subhuman primatized or humanized. Furthermore, these antibodies, fragments or fusion proteins can be selected from the group consisting of intact IgG, F(ab′)2, F(ab)2, Fab′, Fab, scFvs, diabodies, triabodies or tetrabodies and can be conjugated to at least one therapeutic agent.

In accordance with another aspect of the present invention, a method is provided as described above, wherein mammalian subjects, such as humans and domestic or companion animals, are treated with one or more antibodies that are conjugated to one or more therapeutic agents selected from the group consisting of drug, toxin, immunomodulator, chelator, boron compounds, photodynamic agent, and radionuclide.

In yet another preferred embodiment, the therapeutic composition comprises a fusion protein of said combination of antibodies or antibodies with immunomodulators. The fused antibodies can comprise antibodies against different antigens as well as antibodies against different epitopes of the same antigen.

The present invention contemplates the above-mentioned method wherein the conjugated and unconjugated antibody is an anti-CD22 monoclonal that is parenterally administered into a mammal at a preferable dosage of 20-600 milligrams protein per dose, more preferably at 20-150 milligrams protein per dose, and most preferably, at 20-100 milligrams protein per dose. In addition, the mammal may receive the anti-CD22 antibody as repeated parenteral dosages of preferably 20-150 milligrams protein per dose and more preferably, 20-100 mg protein per dose. It is important to recognize that such doses are given as the actual therapeutic dose without requiring any predosing, either for improving targeting or for dosimetric purposes, as practiced previously by, for example, Juweid et al., Clin. Cancer Res. 5:3292s-3303s, 1999 (where a prior dose of 50 mg of the CD22 Mab conjugated with 111In or another diagnostic isotope was required). No attempt was made in such studies to assess the ability of the therapeutic radioimmunoconjugate with various protein doses of the antibody to be effective directly without a prior dosing regimen.

In another preferred embodiment, the method for treating a disease in a mammal comprises administering to the mammal a therapeutic composition comprising a pharmaceutically acceptable vehicle and a multispecific multivalent antibody, fragment or fusion protein conjugate that binds to at least one target antigen and a therapeutic agent, wherein predosing with a non-radiolabeled antibody is not performed.

In yet another preferred embodiment, the method for treating a disease in mammals comprises:

(a) administering to the mammal a composition that comprises a multispecific multivalent antibody, fragment or fusion protein that binds to at least one target antigen;

(b) optionally, a clearing agent to allow the composition to clear non-localized antibodies from circulation; and

(c) administering to the mammal a pharmaceutially effective amount of therapeutic conjugate that binds to the multispecific multivalent antibody, fragment or fusion protein,

and wherein predosing with a non-radiolabeled antibody is not performed.

Other objects, features and advantages of the present invention will become apparent from the following detailed description and appended claims.

DETAILED DESCRIPTION

OF THE PREFERRED EMBODIMENTS

Unless otherwise specified, “a” or “an” means “one or more”.

1. Definitions

In the description that follows, a number of terms are used and the following definitions are provided to facilitate understanding of the present invention.

Non-Hodgkin\'s lymphoma (NHL) refers to a family of lymphoma diseases that involves lymph nodes, spleen, other organs and often the bone marrow There are at least 30 different types of NHL. The two common types are follicular (low grade or indolent) and aggressive, diffuse large cell (intermediate or high grade) lymphomas.

An antibody, as described herein, refers to a full-length (i.e., naturally occurring or formed by normal immunoglobulin gene fragment recombinatorial processes) immunoglobulin molecule (e.g., an IgG antibody) or an immunologically active (i.e., specifically binding) portion of an immunoglobulin molecule, like an antibody fragment.

An antibody fragment is a portion of an antibody such as F(ab′)2, F(ab)2, Fab′, Fab, Fv, sFv and the like. Regardless of structure, an antibody fragment binds with the same antigen that is recognized by the intact antibody. For example, an anti-CD22 monoclonal antibody fragment binds with an epitope of CD22. The term “antibody fragment” also includes any synthetic or genetically engineered protein that acts like an antibody by binding to a specific antigen to form a complex. For example, antibody fragments include isolated fragments consisting of the variable regions, such as the “Fv” fragments consisting of the variable regions of the heavy and light chains, recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker (“scFv proteins”), and minimal recognition units consisting of the amino acid residues that mimic the hypervariable region.

A naked or cold antibody is generally an entire antibody which is not conjugated (unconjugated) to a therapeutic agent. This is so because the Fc portion of the antibody molecule provides effector functions, such as complement fixation and ADCC (antibody dependent cell cytotoxicity), which set mechanisms into action that may result in cell lysis. However, it is possible that the Fc portion is not required for therapeutic function, with other mechanisms, such as apoptosis, coming into play. Naked antibodies are also non-radiolabeled antibodies that include both polyclonal and monoclonal antibodies, as well as certain recombinant antibodies, such as primatized subhuman, chimeric, humanized or human antibodies.

A chimeric antibody is a recombinant protein that contains the variable domains including the complementarity determining regions (CDRs) of an antibody derived from one species, preferably a rodent antibody, while the constant domains of the antibody molecule is derived from those of a human antibody. For veterinary applications, the constant domains of the chimeric antibody may be derived from that of other species, such as a cat or dog.

A humanized antibody is a recombinant protein in which the CDRs from an antibody from one species; e.g., a rodent antibody, is transferred from the heavy and light variable chains of the rodent antibody into human heavy and light variable domains. The constant domains of the antibody molecule is derived from those of a human antibody.

A human antibody is an antibody obtained from transgenic mice that have been “engineered” to produce specific human antibodies in response to antigenic challenge. In this technique, elements of the human heavy and light chain locus are introduced into strains of mice derived from embryonic stem cell lines that contain targeted disruptions of the endogenous heavy chain and light chain loci. The transgenic mice can synthesize human antibodies specific for human antigens, and the mice can be used to produce human antibody-secreting hybridomas. Methods for obtaining human antibodies from transgenic mice are described by Green et al., Nature Genet. 7:13 (1994), Lonberg et al., Nature 368:856 (1994), and Taylor et al., Int. Immun. 6:579 (1994). A fully human antibody also can be constructed by genetic or chromosomal transfection methods, as well as phage display technology, all of which are known in the art. See for example, McCafferty et al., Nature 348:552-553 (1990) for the production of human antibodies and fragments thereof in vitro, from immunoglobulin variable domain gene repertoires from unimmunized donors. In this technique, antibody variable domain genes are cloned in-frame into either a major or minor coat protein gene of a filamentous bacteriophage, and displayed as functional antibody fragments on the surface of the phage particle. Because the filamentous particle contains a single-stranded DNA copy of the phage genome, selections based on the functional properties of the antibody also result in selection of the gene encoding the antibody exhibiting those properties. In this way, the phage mimics some of the properties of the B cell. Phage display can be performed in a variety of formats, for their review, see e.g. Johnson and Chiswell, Current Opiniion in Structural Biology 3:5564-571 (1993).

Human antibodies may also be generated by in vitro activated B cells. See U.S. Pat. Nos. 5,567,610 and 5,229,275, which are incorporated in their entirety by reference.

A therapeutic agent is a molecule or atom which is administered separately, concurrently or sequentially with an antibody moiety or conjugated to an antibody moiety, i.e., antibody or antibody fragment, or a subfragment, and is useful in the treatment of a disease. Examples of therapeutic agents include antibodies, antibody fragments, drugs, toxins, nucleases, hormones, immunomodulators, chelators, boron compounds, photoactive agents or dyes and radioisotopes.

An immunomodulator is a therapeutic agent as defined in the present invention that when present, alters, suppresses or stimulates the body\'s immune system. Typically, the immunomodulator useful in the present invention stimulates immune cells to proliferate or become activated in an immune response cascade, such as macrophages, B-cells, and/or T-cells.

An immunoconjugate is a conjugate of an antibody component with a therapeutic or diagnostic agent. The diagnostic agent can comprise a radioactive or non-radioactive label, a contrast agent (such as for magnetic resonance imaging, computed tomography or ultrasound), and the radioactive label can be a gamma-, beta-, alpha-, Auger electron-, or positron-emitting isotope.

An expression vector is a DNA molecules comprising a gene that is expressed in a host cell. Typically, gene expression is placed under the control of certain regulatory elements, including constitutive or inducible promoters, tissue-specific regulatory elements and enhancers. Such a gene is said to be “operably linked to” the regulatory elements.

A recombinant host may be any prokaryotic or eukaryotic cell that contains either a cloning vector or expression vector. This term also includes those prokaryotic or eukaryotic cells, as well as an transgenic animal, that have been genetically engineered to contain the cloned gene(s) in the chromosome or genome of the host cell or cells of the host cells. Suitable mammalian host cells include myeloma cells, such as SP2/0 cells, and NSO cells, as well as Chinese Hamster Ovary (CHO) cells, hybridoma cell lines and other mammalian host cell useful for expressing antibodies. Also particularly useful to express mAbs and other fusion proteins, is a human cell line, PER.C6 disclosed in WO 0063403 A2, which produces 2 to 200-fold more recombinant protein as compared to conventional mammalian cell lines, such as CHO, COS, Vero, Hela, BHK and SP2-cell lines. Special transgenic animals with a modified immune system are particularly useful for making fully human antibodies.

As used herein, the term antibody fusion protein is a recombinantly produced antigen-binding molecule in which two or more of the same or different single-chain antibody or antibody fragment segments with the same or different specificities are linked. Valency of the fusion protein indicates how many binding arms or sites the fusion protein has to a single antigen or epitope; i.e., monovalent, bivalent, trivalent or mutlivalent. The multivalency of the antibody fusion protein means that it can take advantage of multiple interactions in binding to an antigen, thus increasing the avidity of binding to the antigen. Specificity indicates how many antigens or epitopes an antibody fusion protein is able to bind; i.e., monospecific, bispecific, trispecific, multispecific. Using these definitions, a natural antibody, e.g., an IgG, is bivalent because it has two binding arms but is monospecific because it binds to one epitope. Monospecific, multivalent fusion proteins have more than one binding site for an epitope but only binds with one epitope, for example a diabody with two binding site reactive with the same antigen. The fusion protein may comprise a single antibody component, a multivalent or multispecific combination of different antibody components or multiple copies of the same antibody component. The fusion protein may additionally comprise an antibody or an antibody fragment and a therapeutic agent. Examples of therapeutic agents suitable for such fusion proteins include immunomodulators (“antibody-immunomodulator fusion protein”) and toxins (“antibody-toxin fusion protein”). One preferred toxin comprises a ribonuclease (RNase), preferably a recombinant RNase.

A multispecific antibody is an antibody that can bind simultaneously to at least two targets that are of different structure, e.g., two different antigens, two different epitopes on the same antigen, or a hapten and/or an antigen or epitope. One specificity would be for a B-cell, T-cell, myeloid-, plasma-, and mast-cell antigen or epitope. Another specificity could be to a different antigen on the same cell type, such as CD3, CD4, CD5, CD8, CD11c, CD14, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD33, CD37, CD38, CD40, CD4OL, CD52, CD54, CD74, CD80, CD126, Ia, HMI.24, HLA-DR, tenascin, MUC1 and a B-cell-tumor-associated antigen, including vascular endothelial antigens, such as VEGF and P1GF. Multispecific, multivalent antibodies are constructs that have more than one binding site, and the binding sites are of different specificity. For example, a diabody, where one binding site reacts with one antigen and the other with the another antigen.

A bispecific antibody is an antibody that can bind simultaneously to two targets which are of different structure. Bispecific antibodies (bsAb) and bispecific antibody fragments (bsFab) have at least one arm that specifically binds to, for example, a B-cell, T-cell, myeloid-, plasma-, and mast-cell antigen or epitope and at least one other arm that specifically binds to a targetable conjugate that bears a therapeutic or diagnostic agent. A variety of bispecific fusion proteins can be produced using molecular engineering. In one form, the bispecific fusion protein is monovalent, consisting of, for example, a scFv with a single binding site for one antigen and a Fab fragment with a single binding site for a second antigen. In another form, the bispecific fusion protein is divalent, consisting of, for example, an IgG with a binding site for one antigen and two scFv with two binding sites for a second antigen.

Caninized or felinized antibodies are recombinant proteins in which rodent (or another species) complementarity-determining regions of a monoclonal antibody have been transferred from heavy and light variable chains of rodent (or another species) immunoglobulin into a dog or cat, respectively, immunoglobulin variable domain.

Subhuman primatized antibodies are recombinant proteins in which subhuman primate (e.g., monkey) complementarity-determining regions of a monoclonal antibody have been transferred from heavy and light varian chains of roden (or another species) immunoglobulin into a subhuman primate immunoglobulin variable domain.

Domestic animals include large animals such as horses, cattle, sheep, goats, llamas, alpacas, and pigs, as well as companion animals. In a preferred embodiment, the domestic animal is a horse.



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stats Patent Info
Application #
US 20140147382 A1
Publish Date
05/29/2014
Document #
14168710
File Date
01/30/2014
USPTO Class
424/149
Other USPTO Classes
4241781, 4241721, 4241731, 4241331, 4241421, 4241531, 4241361
International Class
07K16/28
Drawings
0


Antibodies
Antibody
Autoimmune
Autoimmune Diseases
Autoimmune Disease
Fusion
Immunotherapy
Mammal
Proteins
Concurrent
Diseases
Immune Disease
Immune Diseases


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