WO2008014583A1 - Cancerous disease modifying antibodies - Google Patents
Cancerous disease modifying antibodies Download PDFInfo
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- WO2008014583A1 WO2008014583A1 PCT/CA2006/001879 CA2006001879W WO2008014583A1 WO 2008014583 A1 WO2008014583 A1 WO 2008014583A1 CA 2006001879 W CA2006001879 W CA 2006001879W WO 2008014583 A1 WO2008014583 A1 WO 2008014583A1
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- monoclonal antibody
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3015—Breast
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
- C07K16/3069—Reproductive system, e.g. ovaria, uterus, testes, prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Definitions
- This invention relates to the isolation and production of cancerous disease modifying antibodies (CDMAB) and to the use of these CDMAB in therapeutic and diagnostic processes, optionally in combination with one or more chemotherapei. tic agents.
- the invention further relates to binding assays which utilize the CDMABs of the instant invention.
- cancerous arid normal cells contain antigens that are specific to transformed cells
- monoclonal antibodies can be designed to specifically target transformed cells by binding specifically to these caniier antigens; thus giving rise to the belief that monoclonal antibodies can serve as "Magic Bullets" to eliminate cancer cells.
- Monoclonal antibodies isolated in accordance with the teachings of the instantly disclosed invention have been shown to modify the cancerous disease process in a manner which is beneficial to the patient, for example by reducing the tumor burden, and will variously be referred to herein as cancerous disense modifying antibodies (CDMAB) or "anti-cancer" antibodies.
- CDMAB cancerous disense modifying antibodies
- the cancer patient usually has few options of treatment.
- the regimented approach to cancer therapy has produced improvements i i global survival and morbidity rates.
- these improved statistics do not necessarily correlate with an improvement in their persomil situation.
- U.S. Patent No. 5,750,102 discloses a process wherein cells from a patient's tumor are transfected with MHC genes which may be cloned from cells or tissue from the patient. These transfected cells are then used to vaccinate the patient.
- U.S. Patent No. 5,750,102 discloses a process wherein cells from a patient's tumor are transfected with MHC genes which may be cloned from cells or tissue from the patient. These transfected cells are then used to vaccinate the patient.
- 4,861,581 discloses a process comprising the steps of obtaining monoclonal antibodies that are specific to an internal cellular component of neoplastic and normal cells of the mammal but not to external components, labeling the monoclonal antibody, contacting the labeled antibody with tissue of a mammal that has received therapy to kill neoplastic cells, and determining the effectiveness of therap ⁇ by measuring the binding of the labeled antibody to the internal cellular component of 1 ie degenerating neoplastic cells.
- the patentee recognizes that malignant cells represent a convenient source of such antigens.
- U.S. Patent No. 5,171,665 provides a novel antibody and method for its production. Specifically, the patent teaches formation of a monoclonal antibody wh ch has the property of binding strongly to a protein antigen associated with human tumors, e.g. those of the colon and lung, while binding to normal cells to a much les >er degree.
- U.S. Patent No. 5,484,596 provides a method of cancer therapy comprising surgically removing tumor tissue from a human cancer patient, treating the tumor tissue to obtain tumor cells, irradiating the tumor cells to be viable but non- tumorigenic, and using these cells to prepare a vaccine for the patient capable of inhibiting recurrence of the primary tumor while simultaneously inhibiting metastases.
- the patent teaches the development of monoclonal antibodies which are reactive witl surface antigens of tumor cells. As set forth at col. 4, lines 45 et seq., the patentees utilize autochthonous tumor cells in the development of monoclonal antibodies expressing active specific immunotherapy in human neoplasia.
- U.S. Patent No. 5,693,763 teaches a glycoprotein antigen characteristic of human carcinomas and not dependent upon the epithelial tissue of origin.
- U.S. Patent No. 5,783,186 is drawn to Anti-Her2 antibodies which induce apoptosis in Her2 expressing cells, hybridoma cell lines producing the antibodies, methods of treating cancer using the antibodies and pharmaceutical compositions including said antibodies.
- U.S. Patent No. 5,849,876 describes new hybridoma cell lines for the production of monoclonal antibodies to mucin antigens purified from tumor and non tumor tissue sources.
- U.S. Patent No. 5,869,268 is drawn to a method for generating a hum .in lymphocyte producing an antibody specific to a desired antigen, a method for producing a monoclonal antibody, as well as monoclonal antibodies produced by the method.
- the patent is particularly drawn to the production of an anti-HD human monoclonal antibody useful for the diagnosis and treatment of cancers.
- U.S. Patent No. 5,869,045 relates to antibodies, antibody fragments, antibody conjugates and single chain immunotoxins reactive with human carcinoma cells.
- the mechanism by which these antibodies function is two-fold, in that the molecules are reactive with cell membrane antigens present on the surface of human carcinomas, and further in that the antibodies have the ability to internalize within tli :: carcinoma cells, subsequent to binding, making them especially useful for forming antibody-drug and antibody-toxin conjugates.
- the antibodies In their unmodified form the antibodies also manifest cytotoxic properties at specific concentrations.
- U.S. Patent No. 5,780,033 discloses the use of autoantibodies for turn ;>r therapy and prophylaxis.
- this antibody is an antinuclear autoantibody fron an aged mammal.
- the autoantibody is said to be one type of natural antibody found in the immune system. Because the autoantibody comes from "an aged mammal", there is no requirement that the autoantibody actually comes from the pal ient being treated.
- the patent discloses natural and monoclonal antinuclear autoantibody from an aged mammal, and a hybridoma cell line producing a monoclonal antinuclear autoantibody.
- This application utilizes methods for producing patient specific anticancer antibodies as taught in the '357 patent for isolating hybridoma cell lines which encode for cancerous disease modifying monoclonal antibodies. These antibodies can be made specifically for one tumor and thus make possible the customization of cancer therapy.
- anti-cancer antibodies having either cell-killing (cytotoxic) or cell-growth inhibiting (cytostatic) properties will hereafter be referred to as cytotoxic. These antibodies can be used in aid of staging and diagnosis of a cancer, and can be used to treat tumor metastases.
- a likely clinical scenario is that a tumor sample is obtained at the time of presentation, and banked. From this sample, the tumor can be typed from a panel of pre-existing cancerous disease modifying antibodies.
- the patient will be conventionally staged but the available antibodies ca i be of use in further staging the patient.
- the patient can be treated immediately with the existing antibodies, and a panel of antibodies specific to the tumor can be produced either using the methods outlined herein or through the use of phage display libraries in conjunction with the screening methods herein disclosed.
- All the antibodies general id will be added to the library of anti-cancer antibodies since cross-reactivity may occur, in other words there is a possibility that other tumors can bear some of the same epitopes as the one that is being treated.
- the antibodies produced according to this method may be useful to treat cancerous disease in any number of patients who have cancers that bind to these antibodies.
- the patient can elect to receive the currently recommended therapies as part of a multi-modal regimen of treatment.
- Th ⁇ fact that the antibodies isolated via the present methodology are relatively non-toxic o non-cancerous cells allows for combinations of antibodies at high doses to be used, either alone, or in conjunction with conventional therapy.
- the high therapeutic inde>. will also permit re-treatment on a short time scale that should decrease the likelihood of emergence of treatment resistant cells.
- the process of generating specific antibodies to the tumor can be repeated fi >r re-treatment.
- the anti-cancer antibodies can be conjugated to red blood cells obtained from that patient and re-infused for treatment of metastases.
- metastatic cancers are usually well vascularized and the delivery of anti-cancer antibodies by red blood cells can have ti e effect of concentrating the antibodies at the site of the tumor.
- red blood cells Even prior to metastases, most cancer cells are dependent on the host's blood supply for their survival and anti cancer antibody conjugated to red blood cells can be effective against in situ tumors iis well.
- the antibodies may be conjugated to other hematogenous cells, o.g. lymphocytes, macrophages, monocytes, natural killer cells, etc.
- Murine antibodies of the IgG2a ⁇ ind IgG3 isotype are effective at recruiting cytotoxic cells that have Fc receptors which 'vill lead to cell killing by monocytes, macrophages, granulocytes and certain lymphocytes.
- Human antibodies of both the IgGl and IgG3 isotype mediate ADCC.
- Another possible mechanism of antibody mediated cancer killing may be through the use of antibodies that function to catalyze the hydrolysis of various chemical bonds in the cell membrane and its associated glycoproteins or glycolipids, so-called catalytic antibodies.
- catalytic antibodies There are two additional mechanisms of antibody mediated cancer eel I killing which are more widely accepted.
- the first is the use of antibodies as a vaccine to induce the body to produce an immune response against the putative cancer antigen that resides on the tumor cell.
- the second is the use of antibodies to target growth receptors and interfere with their function or to down regulate that receptor so that effectively its function is lost.
- cancerous disease modifying antibodies whose cytotoxicity is a function of their ability to catal j/ze hydrolysis of cellular chemical bonds.
- a still further objective of the instant invention is to produce cancerous disease modifying antibodies which are useful for in a binding assay for diagnosis, prognosis, and monitoring of cancer.
- Figure 1 includes representative FACS histograms of 1 A245.6 antibodies, isotype control antibodies for both antibodies, anti-EGFR antibodies directed against several cancer cell lines and non-cancer cells;
- Figure 2 includes representative FACS histograms of 7BD-33- 1 1 A antibodies, isotype control antibodies for 1 A245.6, anti-EGFR antibodies, isotype control antibodies for anti-EGFR directed against several cancer cell lines and non- cancer cells;
- Figure 3 includes representative FACS histograms of 1 1BD-2E1 1-2 antibodies, isotype control antibodies for both antibodies, anti-EGFR antibodies directed against several cancer cell lines and non-cancer cells;
- Figure 4 is a graphical analysis of tumor volume over time with respect to particular antibody treatment;
- Figure 5 is a graphical analysis of antibody effect on MB231 Human Breast Cancer tumor volume over time;
- Figure 6 is a graphical analysis quantifying percent survival over time 1 relative to antibody therapy.
- antibody is used in the broadest sense and specifically covers, for example, single monoclonal antibodies (including agonist, antagonist, anil neutralizing antibodies, de-immunized, murine, chimerized or humanized antibodies ⁇ , antibody compositions with polyepitopic specificity, single-chain antibodies, immunoconjugates and fragments of antibodies (see below).
- the term "monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies a re highly specific, being directed against a single antigenic site. Furthermore, in contract to polyclonal antibody preparations which include different antibodies directed agaii ist different determinants (epitopes), each monoclonal antibody is directed against a sir E ⁇ le determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they may be synthesized uncontaminated by other antibodk s.
- the modifier "monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
- the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma (murine or human) method first described by Kohler et ah, Nature, 256:495 (1975), or may be made by recombinant DNA methods (see, e.g., I I.S. Pat. No.4,816,567).
- the "monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature, 352:624- 628 (1991) and Marks et al., J. MoI. Biol, 222:581-597 (1991), for example.
- Antibody fragments comprise a portion of an intact antibody, preferably comprising the antigen-binding or variable region thereof.
- antibody fragments include less than full length antibodies, Fab, Fab', F(ab') 2 , and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules; single-chain antibodies, single domain antibody molecules, fusion proteins, recombinant proteins and multispecif ⁇ c antibodies formed from antibody fragment(s).
- an “intact” antibody is one which comprises an antigen-binding varia I)Ie region as well as a light chain constant domain (C L ) and heavy chain constant domains, C H I , C H 2 and CH3.
- the constant domains may be native sequence constant domains (e.g. human native sequence constant domains) or amino acid sequence variant thereof.
- the intact antibody has one or more effector functions.
- intact antibodies can be assigned to different "classes". There are five- major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into “subclasses” (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgA, and IgA2.
- the heavy-chain constant domains that correspond to the different classes of antibodies are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
- the subunit structures and three- dimensional configurations of different classes of immunoglobulins are well known.
- Antibody effector functions refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody.
- Examples of antibody effector functions include C Iq binding; complement dependent cytotoxicity; Fc receptor binding; antibody-dependc nt cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g. B cell receptor; BCR), etc.
- Antibody-dependent cell-mediated cytotoxicity and “ADCC” refer Io a cell-mediated reaction in which nonspecific cytotoxic cells that express Fc recepto s (FcRs) (e.g. Natural Killer (NK) cells, neutrophils, and macrophages) recognize bou id antibody on a target cell and subsequently cause lysis of the target cell.
- FcRs Fc recepto s
- the primary cells for mediating ADCC, NK cells express Fc ⁇ RIII only, whereas monocytes expitess Fc ⁇ RI, Fc ⁇ RII and Fc ⁇ RIII.
- FcR expression on hematopoietic cells in summarized i ⁇ Table 3 on page 464 of Ravetch and Kinet, ⁇ n « «. Rev.
- Tc assess ADCC activity of a molecule of interest
- an in vitro ADCC assay such as that described in U.S. Pat. No. 5,500,362 or 5,821,337
- Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells.
- PBMC peripheral blood mononuclear cells
- NK Natural Killer
- ADCC activity of the molecule of interest may be assessed in vivo, e.g., in a animal model such as that disclosed in Clynes et al. PNAS (USA) 95:652-656 (1998).
- “Effector cells” are leukocytes which express one or more FcRs and perform effector functions. Preferably, the cells express at least Fc ⁇ RIII and perform ADCC effector function. Examples of human leukocytes which mediate ADCC include peripheral blood mononuclear cells (PBMC), natural killer (NK) cells, monocytes, cytotoxic T cells and neutrophils; with PBMCs and NK cells being preferred.
- the effector cells may be isolated from a native source thereof, e.g. from blood or PBMC s as described herein.
- the terms "Fc receptor” or “FcR” are used to describe a receptor that binds to the Fe region of an antibody.
- the preferred FcR is a native sequence human FcR.
- a preferred FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII subclasses, including allelic variants and alternatively spliced forms of these receptors.
- Fc ⁇ RII receptors include Fc ⁇ RIIA (an “activating receptor") and Fc ⁇ RIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof.
- Activating receptor Fc ⁇ RIIA contains an immunorece ⁇ tor tyrosine-based activation motif (ITAM) in its cytoplasmic domain.
- ITAM immunorece ⁇ tor tyrosine-based activation motif
- Inhibiting receptor Fc ⁇ RIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain, (see review M. in Dagron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al, Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. CHr/. Med 126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term "FcR" herein.
- ITIM immunoreceptor tyrosine-based inhibition motif
- the term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et ai., J. Immunol. 1 17:587 (1976) and Kim et al, Eur. J. Immunol. 24:2429 (1994)).
- “Complement dependent cytotoxicity” or “CDC” refers to the ability of a molecule to lyse a target in the presence of complement.
- the complement activation pathway is initiated by the binding of the first component of the complement system (CIq) to a molecule (e.g. an antibody) complexed with a cognate antigen.
- a CDC assay e.g. as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996) may be performed.
- variable refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not evenly distributed throughout the variable domains of antibodies. It is concentrated in three segments called hypervariable regions both in the light chain ai d the heavy chain variable domains. The more highly conserved portions of variable domains are called the framework regions (FRs).
- the variable domains of native hea ⁇ >y and light chains each comprise four FRs, largely adopting a ⁇ -sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases forming part of, the >sheet structure.
- the constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody dependent cellular cytotoxicity (ADCC).
- hypervariable region when used herein refers to the amino acid residues of an antibody which are responsible for antigen-binding.
- the hypervariable region generally comprises amino acid residues from a "complementarity determining region” or "CDR" (e.g. residues 24-34 (Ll), 50-56 (L2) and 89-97 (L3) in the light chain variable domain and 31-35 (Hl), 50-65 (H2) and 95-102 (H3) in the heavy chain variable domain; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.
- CDR complementarity determining region
- Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual "Fc” fragment, whose name reflects its ability to crystallize readily. Pepsin treatment yields an F(ab') 2 fragment that has two antigen-binding sites and is still capable of cross-linking antigen.
- Fv is the minimum antibody fragment which contains a complete antigen-recognition and antigen-binding site. This region consists of a dimer of one heavy chain and one light chain variable domain in tight, non-covalent association. Il is in this configuration that the three hypervariable regions of each variable domain interact to define an antigen-binding site on the surface of the V H -V L dimer. Collectively, the six hypervariable regions confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three hypervariable regions specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
- the Fab fragment also contains the constant domain of the light chain and the first constant domain (CH I) of the heavy chain.
- Fab' fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CHl domain including one or m :>re cysteines from the antibody hinge region.
- Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear at least one free thiol group.
- F(ab') 2 antibody fragments originally were produced as pairs of Fab' fragments whic i have hinge cysteines between them. Other chemical couplings of antibody fragment;: are also known.
- the "light chains" of antibodies from any vertebrate species can be assigned to one of two clearly distinct types, called kappa (K) and lambda ( ⁇ ), based on the amino acid sequences of their constant domains.
- Single-chain Fv or “scFv” antibody fragments comprise the V H and V L domains of antibody, wherein these domains are present in a single polypeptide chai n.
- the Fv polypeptide further comprises a polypeptide linker between the V i and V L domains which enables the scFv to form the desired structure for antigen binding.
- diabodies refers to small antibody fragments with two antigen-binding sites, which fragments comprise a variable heavy domain (V H ) connected to a variable light domain (V L ) in the same polypeptide chain (V H -V L ). using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chnin and create two antigen-binding sites.
- Diabodies are described more fully in, for example, EP 404,097; WO 93/1 1 161 ; and Hollinger et al, Proc. Natl. Acad. ScL USA, 90:6444-6448 (1993).
- Isolated antibody is one which has been identified and separatee and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones and other protcinaceous or nonproteinaceous solutes. Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will ;>e prepared by at least one purification step.
- An antibody "which binds" an antigen of interest is one capable of binding that antigen with sufficient affinity such that the antibody is useful as a therapeutic or diagnostic agent in targeting a cell expressing the antigen.
- the antibody is one which binds the antigenic moiety it will usually preferentially bind that antigenic moiety as opposed to other receptors, and does not include incidental binding such as non-specific Fc contact, or binding to post-translational modifications common to other antigens and may be one which does not significantly cross-react with other proteins.
- Methods, for the detection of an antibody that binds an antigen of interest ..ire well known in the art and can include but are not limited to assays such as FACS, cell ELISA and Western blot.
- assays such as FACS, cell ELISA and Western blot.
- progeny may not be precisely identical in DNA content, due to deliberate or inadvertent mutations. Mutant progeny that have the same function or biological activity as screened for in the originally transformed cell are included. It will be cleai from the context where distinct designations are intended.
- Treatment refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder.
- Those in need of treatment include those already with the disorder as well as those prone to have the disorder or those in whoi n the disorder is to be prevented.
- the mammal to be treated herein may have be .:n diagnosed as having the disorder or may be predisposed or susceptible to the disorde r.
- cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth or death.
- cancer examples include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g. epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, can ⁇ r of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer.
- squamous cell cancer e.g
- chemotherapeutic agent is a chemical compound useful in the treatment of cancer.
- examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXANTM); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretami ⁇ e, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, tro
- paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel (TAXOTERE®, Aventis, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-1 1 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of
- anti-hormonal agents that act to regulate or inhibit hormone action on tumors
- anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LYl 17018, onapristone, and toremifene (Fareston); and anti- androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
- “Mammal” for purposes of treatment refers to any animal classified ai a mammal, including humans, mice, SCID or nude mice or strains of mice, domestic a id farm animals, and zoo, sports, or pet animals, such as sheep, dogs, horses, cats, cows;, etc.
- the mammal herein is human.
- Oligonucleotides are short-length, single- or double-stranded polydeoxynucleotides that are chemically synthesized by known methods (such as phosphotriester, phosphite, or phosphoramidite chemistry, using solid phase techniques such as described in EP 266,032, published 4 May 1988, or via deoxynucleoside H- phosphonate intermediates as described by Froehler et al., Nucl. Acids Res., 14:5399- 5407, 1986. They are then purified on polyacrylamide gels.
- “Chimeric” antibodies are immunoglobulins in which a portion of thi: heavy and/or light chain is identical with or homologous to corresponding sequence;; in antibodies derived from a particular species or belonging to a particular antibody cla -,s or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long sis they exhibit the desired biological activity (U.S. Pat. No. 4,816,567 and Morrison et al, Proc. Natl. Acad. ScL USA, 81 :6851-6855 (1984)).
- Humanized forms of non-human (e.g. murine) antibodies are speci lic chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab) 2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin.
- humanized antibodies are human immunoglobulins (recipient antibody) in which residues from the complementarity determining regions (CDRs) of the recipient antibody are replaced by residues from the CDRs of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity.
- Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human FR residues.
- the humanized antibody may comprise residues which are found neither in the recipient antibody nor in the imported CDR or FR sequences. These modifications are made tc further refine and optimize antibody performance.
- the humanized antibod y will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-humati immunoglobulin and all or substantially all of the FR residues are those of a human immunoglobulin consensus sequence.
- the humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
- De-immunized antibodies are immunoglobulins that are non- immunogenic, or less immunogenic, to a given species. De- immunization can be achieved through structural alterations to the antibody. Any de- immunization technique known to those skilled in the art can be employed. One suitable technique for de- immunizing antibodies is described, for example, in WO 00/34317 published June 15, 2000.
- An antibody which induces "apoptosis” is one which induces programmed cell death by any menas, illustrated by but not limited to binding of annexin V, caspase activity, fragmentation of DNA, cell shrinkage, dilation of endoplasmic reticulum, cell fragmentation, and/or formation of membrane vesicles (called apoptotic bodies).
- hybridoma cell lines as well as the isolated monoclonal antibodies which are produced therefrom, are alternatively refeired to by their internal designation, 7BD-33-1 IA, 1 A245.6 or 11BD-2E11-2, or Depositary Designation, ATCC Number PTA-4890, PTA-4889, or PTA-5643 respectively.
- antibody-ligand includes a moiety which exhibits binding specificity for at least one epitope of the target antigen, and which may be aiii intact antibody molecule, antibody fragments, and any molecule having at least an antigen-binding region or portion thereof (i.e., the variable portion of an antibody molecule), e.g., an Fv molecule, Fab molecule, Fab 1 molecule, F(ab').sub.2 molecule, a bispecific antibody, a fusion protein, or any genetically engineered molecule which specifically recognizes and binds at least one epitope of the antigen bound by the isolated monoclonal antibody produced by the hybridoma cell line designated as ATCC Number PTA-4890, PTA-4889, or PTA-5643 respectively ( the ATCC Number PTA- 4890, PTA-4889, or PTA-5643 antigen).
- CDMAB cancerous disease modif ⁇ ying antibodies
- antigen-binding region means a portion of the molecule which recognizes the target antigen.
- target antigen is the ATCC Number PTA-4890, PTA- 4889, or PTA-5643 antigen respectively, or portions thereof.
- an "immunoconjugate” means any molecule or CDMAB such as an antibody chemically or biologically linked to a cytotoxin, a radioactive agent, enzyme, toxin, an anti-tumor drug or a therapeutic agent.
- the antibody or CDMAB may be linked to the cytotoxin, radioactive agent, anti-tumor drug or therapeutic agent at any location along the molecule so long as it is able to bind its target.
- Examples of immunoconjugates include antibody toxin chemical conjugates and antibody-toxin fusion proteins.
- fusion protein means any chimeric protein wherein an antigen binding region is connected to a biologically active molecule, e.g., toxin, enzyme, or protein drug.
- the CDMAB of the invention may be modified, i.e., by amino acid modifications within the molecule, so as to produce derivative molecules. Chemical modification may also be possible. Derivative molecules would retain the functional property of the polypeptide, namely, the molecule having such substitutions will still permit the binding of the polypeptide to the ATCC Number PTA-4890, PTA-4889, or PTA-5643 antigen, respectively, or portions thereof. These amino acid substitutions include, but are not necessarily controlc to, amino acid substitutions known in the art as "conservative".
- Such changes include substituting any of isoleucine (I), valine (V), arid leucine (L) for any other of these hydrophobic amino acids; aspartic acid (D) for glutamic acid (E) and vice versa; glutamine (Q) for asparagine (N) and vice versa; ai id serine (S) for threonine (T) and vice versa.
- Other substitutions can also be considers d conservative, depending on the environment of the particular amino acid and its role in the three-dimensional structure of the protein. For example, glycine (G) and alanine A) can frequently be interchangeable, as can alanine and valine (V).
- Methionine (M) which is relatively hydrophobic, can frequently be interchanged with leucine and isoleucine, and sometimes with valine. Lysine (K) and arginine (R) are frequently interchangeable in locations in which the significant feature of the amino acid residue is its charge and the differing pK's of these two amino acid residues are not significant. Still other changes can be considered "conservative" in particular environments.
- hybridoma cell lines 7BD-33-1 IA and 1 A245.6 were deposited, in accordance with the Budapest Treaty, with the American Type Culture Collection, 10801 University Boulevard., Manassas, VA 20110-2209 on January 8, 2003, under Accession Number PTA-4890 and PTA-4889, respectively. In accordance with 37 CFR 1.808, the depositors assure that all restrictions imposed on the availability to the public of the deposited materials will be irrevocably removed upon the granting of a patent.
- the hybridoma cell line 1 1BD-2E1 1 -2 was deposited, in accordance with the Budapest Treaty, with the American Type Culture Collection, 10801 University Boulevard., Manassas, VA 201 10-2209 on November 1 1 , 2003, under Accessic n Number PTA-5643. In accordance with CFR 1.808, the depositors assure that all restrictions imposed on the availability to the public of the deposited materials will bs irrevocably removed upon the granting of a patent.
- IA single cell suspensions of the antigen i.e. human breast cancer cells
- the antigen i.e. human breast cancer cells
- Eight to nine weeks old BALB/c mice were immunized by injecting 100 microliters of the antigen-adjuvant containing between 0.2 million and 2.5 million cells in divided doses both subcutaneously and intraperitoneally with Freund's Complete Adjuvant.
- Freshly prepared antigen-adjuvant was used to boost the immunized mice at between 0.2 million and 2.5 million cells in the same fashion three weeks after the initial immunization, and two weeks after the last boost.
- a spleen WHS used for fusion at least two days after the last immunization.
- the hybridomas were prepared by fusing the isolated splenocytes with Sp2/0 myeloma partners. The supernatants from the fusions were tested for subcloning of the hybridomas. To produce the hybridoma that produce the anti-cancer antibody
- A245.6 single cell suspensions of the antigen i.e. human breast cancer cells, were prepared in cold PBS. Eight to nine weeks old BALB/c mice were immunized by injecting 100 microliters of the antigen-adjuvant containing 2.5 million cells in divided doses both subcutaneously and intraperitoneally with Freund's Complete Adjuvant. Freshly prepared antigen-adjuvant was used to boost the immunized mice at 2.5 million cells in the same fashion three weeks after the initial immunization, two weeks later, five weeks later and three weeks after the last boost. A spleen was used for fusion ai least three days after the last immunization. The hybridomas were prepared by fusing the isolated splenocytes with NSO-I myeloma partners. The supernatants from the fusions were tested for subcloning of the hybridomas.
- the hybridomas we re prepared by fusing the isolated splenocytes with NSO-I myeloma partners. The supernatants from the fusions were tested for subcloning of the hybridomas.
- an ELISA assay was employed. 100 microliters/well of goat anti-mouse IgG + IgM (H+L) at a concentration of 2.4 micrograms/mL in coating buffer (0.1 M carbonate/bicarbonate buffer, pH 9.2-9.6) at 4 0 C was added to the ELI!: A plates overnight. The plates were washed thrice in washing buffer (PBS + 0.05% Tween).
- MDA-MB-231 also referred to as MB-231
- MDA-M B- 468 also referred to as MB-468
- SKBR-3 The plated cells were fixed prior to use. The plates were washed thrice with PBS containing MgCl 2 and CaCl 2 at room temperature. 100 microliters of 2% paraformaldehyde diluted in PBS was added to each well for ten minutes at room temperature and then discarded.
- the plates were washed three times with wash buffer and 100 microliters/well of 1/5000 dilution of goat anti-mouse IgG or IgM antibody conjugal ::d to horseradish peroxidase (diluted in PBS containing 1% bovine serum albumin) wa: added. After a one hour incubation at room temperature the plates were washed thre :: times with wash buffer and 100 microliter/well of TMB substrate was incubated for 1-3 minutes at room temperature. The reaction was terminated with 100 microliters/well 2M H 2 SO 4 and the plate read at 450 nm with a Perkin-Elmer HTS7000 plate reader.
- the results as tabulated in Table 1 were expressed as the number of folds above background compared to the IgG isotype control (3BD-27).
- the antibodies from the 7BD-33-11A and 1A245.6 hybridoma cell lines bound strongly to all 3 breast lines, with binding at least 6 times greater than background. Both antibodies bound most strongly to the MDA-MB-231 cell line.
- the antibodies from the 1 1BD-2E1 1-2 hybridoma cell line also bound most strongly to the MDA-MB-231 cell line, but did not demonstrate binding on the other 2 cell lines greater than background.
- the hybridoma supernatants were tested in the same breast cancer cell lines: MDA-MB- 231, MDA-MB-468 and SKBR-3.
- the Live/Dead cytotoxicity assay was obtained from Molecular Probes (Eu 5 OR). The assays were performed according to the manufacturer's instructions with the changes outlined below. Cells were plated before the assay at the predetermined appropriate density. After 2 days, 100 microliters of supernatant from the hybridoma microtitre plates were transferred to the cell plates ; nd incubated in a 5% CO 2 incubator for 5 days.
- the antibody derived form the hybridoma cell can produce cytotoxicity in cancer cells.
- Monoclonal antibodies were produced by culturing the hybridomas, 7BD-33-1 IA, 1A245.6, 1 1BD-2E1 1-2, in CL-1000 flasks (BD Biosciences, Oakville, ON) with collections and reseeding occurring twice/week and standard antibody purification procedures with Protein G Sepharose 4 Fast Flow (Amersham Biosciences, Baie d'Urfe, QC). It is within the scope of this invention to utilize monoclonal antibodies which are humanized, chimerized or murine antibodies.
- MPC-1 1 antigenic specificity unknown, IgG2b, kappa, 20 microgram/mL
- J6O6 anti-fructosan, IgG3, kappa, 20 microgram/mL
- IgG Buffer 2%) controls in a cytotoxicity assay (Table 2).
- Breast cancer MB-231, MB-468, MCF-7
- colon cancer HT-29, SWl 1 16, SW620
- lung cancer NCI H460
- ovarian cancer OVCAR
- PC-3 ovarian cancer
- non-cancer CCD 27sk, Hs888 Lu
- the Live/Dead cytotoxicity assay was obtained from Molecular Probes (Eugene,OR). The assays were performed according to the manufacturer's instructions with the changes outlined below. Cells were plated befoi :: the assay at the predetermined appropriate density. After 2 days, 100 microliters of purified antibody was diluted into media, and then were transferred to the cell plates and incubated in a 8% CO 2 incubator for 5 days. The plate was then emptied by inverting and blotted dry. Room temperature DPBS containing MgCl 2 and CaCl 2 Wa 1 ; dispensed into each well from a multichannel squeeze bottle, tapped three times, emptied by inversion and then blotted dry.
- the 7BD-33-1 IA and 1 A245.6 antibodies demonstrated cytotoxicity in breast and prostate tumor cell lines selectively, while having no effect on non-transformed normal cells. Both demonstrated a 25-50% greater killing than the positive control anti-Fas antibody.
- 1 1 BD-2E1 1 -2 was specifically cytotoxic in breast and ovarian cancer cells, and did not affect normal cells.
- the chemical cytotoxic agents induced their expected cytotoxicity while a number o other antibodies which were included for comparison also performed as expected the limitations of biological cell assays. In total, it was shown that the three antibodies have cytotoxic activity against a number of cancer cell types. The antibodies were selective in their activity since not all cancer cell types were susceptible. Furthermoi .:, the antibodies demonstrated functional specificity since they did not produce cytotoxicity against non-cancer cell types, which is an important factor in a therapeu .ic situation.
- Cells were prepared for FACS by initially washing the cell monolayer with DPBS (without Ca ⁇ and Mg " ").
- Cell dissociation buffer (INV1TROGEN) wai then used to dislodge the cells from their cell culture plates at 37°C. After centrifugation and collection the cells were resuspended in Dulbecco's phosphate buffered saline containing MgCl 2 , CaCl 2 and 25% fetal bovine serum at 4 0 C (wash media) and counted, aliquoted to appropriate cell density, spun down to pellet the ce Is and resuspended in staining media (DPBS containing MgCl 2 and CaCl 2 ) containing 7BD-33-1 IA, 1 A245.6, 1 1BD-2E1 1-2 or control antibodies (isotype control or anti- EGF-R) at 20 micrograms/mL on ice for 30 minutes.
- staining media DPBS containing MgCl 2 and CaCl 2
- the cells Prior to the addition of Alexa Fluor 488-conjugated secondary antibody the cells were washed once with wash media. The Alexa Fluor 488-conjugated antibody in staining media was then added for 20 minutes. The cells were then washed for the final time and resuspended in staining media containing 1 microgram/mL propidium iodide. Flow cytometric acquisition of the cells was assessed by running samples on a FACScan using the CellQuest softw ⁇ re (BD Biosciences). The forward (FSC) and side scatter (SSC) of the cells were set by adjusting the voltage and amplitude gains on the FSC and SSC detectors.
- FSC forward
- SSC side scatter
- the detectors for the three fluorescence channels were adjusted by running c ⁇ :lls stained with purified isotype control antibody followed by Alexa Fluor 488-conjugaled secondary antibody such that cells had a uniform peak with a median fluorescent intensity of approximately 1-5 units.
- Live cells were acquired by gating for FSC and propidium iodide exclusion. For each sample, approximately 10,000 live cells were acquired for analysis and the resulted presented in Table 3.
- 1 1 BD-2E1 1 -2 displayed specific tumor binding to the breast tumor cell line MDA-MB-231.
- Both 7BD-33-1 IA and 1 A245.6 displayed similar binding to cancer lines of breast (MDA-MB-231 and MCF-7), colon, lung, ovary, arid prostate origin and differential binding to one of the breast cancer cell lines (MDA- MB-468). There was binding of all three antibodies to non-cancer cells, however tha t
- mice four to eight week old, female SCID mice were implanted with 5 million MDA-MB-231 human breast cancer cells in one hundred microliters injected subcutaneously in the scruff c I * the neck. The mice were randomly divided into four treatment groups often. On the
- survival benefits (Fig. 6) from treatment wil h 7BD-33-1 IA, 1A245.6, and 1 1BD-2E1 1-2 cytotoxic antibodies.
- the control group treated with 3BD-27 antibody reached 100% mortality by day 74 post-implantation.
- groups treated with 7BD-33-1 IA were disease free and 1 A245.6 treated animal displayed 100% survival and the group treated with 1 1BD-2E1 1-2 had 24% survival.
- cytotoxic antibody treatment produced a decreased tumor burden and increased survival in comparison to a control antibody in a well recognized model of human cancer disease suggesting pharmacologic and pharmaceutical benefi ts of these antibodies (7BD-33-1 IA, 1A245.6, 1 1 BD-2E1 1-2) for therapy in other mammals, including man.
- EXAMPLE 4 EXAMPLE 4.
- mice Five to six week old, female SCID mice were implanted with 5 million MDA-MB-231 breast cancer cells in one hundred microliters injected subcutaneousl;, in the scruff of the neck. Tumor growth was measured with calipers every week. Wh ⁇ :n the majority of the cohort reached a tumor volume of 100 mm 3 (range 50-200 mm 3 ) J t 34 days post implantation 8-10 mice were randomly assigned into each of three treatment groups.
- 7BD-33-1 1 A, 1 A245.6 test antibodies or 3BD-27 isotype control antibody (known not to bind MDA-MB-231 cells) were administered intrapertioneally with 15 mg/kg of antibodies at a volume of 150 microliters after dilution from the stc ck concentration with a diluent that contained 2.7 mM KCl, 1 mM KH 2 PO 4, 137 mM NaCl, 20 mM Na 2 HPO 4 .
- the antibodies were then administered three times per wee! for 10 doses in total in the same fashion until day 56 post-implantation.
- Tumor growl h was measured about every seventh day with calipers until day 59 post-implantation or until individual animals reached the Canadian Council for Animal Care (CCAC) end ⁇ points. Body weights of the animals were recorded for the duration of the study. At the end of the study all animals were euthanised according to CCAC guidelines.
- CCAC Canadian Council for Animal Care
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AU2006346988A AU2006346988A1 (en) | 2006-08-03 | 2006-11-17 | Cancerous disease modifying antibodies |
MX2009001292A MX2009001292A (en) | 2006-08-03 | 2006-11-17 | Cancerous disease modifying antibodies. |
JP2009522058A JP2009545533A (en) | 2006-08-03 | 2006-11-17 | Cancer-like disease-modifying antibody |
EP06804741A EP2046381A4 (en) | 2006-08-03 | 2006-11-17 | Cancerous disease modifying antibodies |
BRPI0621921-7A BRPI0621921A2 (en) | 2006-08-03 | 2006-11-17 | antibodies that modify cancerous diseases |
CA002658504A CA2658504A1 (en) | 2006-08-03 | 2006-11-17 | Cancerous disease modifying antibodies |
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US6180357B1 (en) * | 1999-10-08 | 2001-01-30 | Arius Research, Inc. | Individualized patient-specific anti-cancer antibodies |
US7009040B2 (en) * | 2003-01-21 | 2006-03-07 | Arius Research, Inc. | Cancerous disease modifying antibodies |
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US4828991A (en) | 1984-01-31 | 1989-05-09 | Akzo N.V. | Tumor specific monoclonal antibodies |
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US5171665A (en) | 1989-04-17 | 1992-12-15 | Oncogen | Monoclonal antibody to novel antigen associated with human tumors |
US6020145A (en) | 1989-06-30 | 2000-02-01 | Bristol-Myers Squibb Company | Methods for determining the presence of carcinoma using the antigen binding region of monoclonal antibody BR96 |
EP0539970B1 (en) | 1991-10-30 | 1999-05-26 | Idemitsu Kosan Company Limited | Methods for producing human lymphocytes and human monoclonal antibodies, and human monoclonal antibodies produced thereby |
IL105008A0 (en) | 1992-03-13 | 1993-07-08 | Yeda Res & Dev | Double transfectants of mhc genes as cellular vaccines for immunoprevention of tumor metastasis |
US5545532A (en) | 1993-02-05 | 1996-08-13 | Epigen, Inc. | Human carcinoma antigen (HCA), HCA antibodies, HCA immunoassays and methods of imaging |
JPH10505819A (en) | 1994-06-24 | 1998-06-09 | ヴラディミール ピー. トーチリン | Use of autoantibodies for treatment and prevention of tumors |
US5783186A (en) | 1995-12-05 | 1998-07-21 | Amgen Inc. | Antibody-induced apoptosis |
US20040105816A1 (en) * | 1999-10-08 | 2004-06-03 | Young David S. F. | Cancerous disease modifying antibodies |
US7431923B2 (en) * | 2005-01-03 | 2008-10-07 | Arius Research Inc. | Cytotoxicity mediation of cells evidencing surface expression of CD63 |
US7534429B2 (en) * | 2000-11-29 | 2009-05-19 | Hoffmann-La Roche Inc. | Cytotoxicity mediation of cells evidencing surface expression of CD63 |
US7361343B2 (en) * | 2003-01-21 | 2008-04-22 | Arius Research Inc. | Cytotoxicity mediation of cells evidencing surface expression of CD63 |
US20060216235A1 (en) * | 2003-01-21 | 2006-09-28 | Young David S F | Cancerous disease modifying antibodies |
US7488475B2 (en) * | 2003-01-21 | 2009-02-10 | Arius Research, Inc. | Antibody therapy of tumors |
US7361342B2 (en) * | 2003-01-21 | 2008-04-22 | Arius Research Inc. | Cancerous disease modifying antibodies |
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US6180357B1 (en) * | 1999-10-08 | 2001-01-30 | Arius Research, Inc. | Individualized patient-specific anti-cancer antibodies |
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