MXPA99011526A - Methods of delaying development of hmfg-associated tumors using anti-idiotype antibody 11d10 - Google Patents
Methods of delaying development of hmfg-associated tumors using anti-idiotype antibody 11d10Info
- Publication number
- MXPA99011526A MXPA99011526A MXPA/A/1999/011526A MX9911526A MXPA99011526A MX PA99011526 A MXPA99011526 A MX PA99011526A MX 9911526 A MX9911526 A MX 9911526A MX PA99011526 A MXPA99011526 A MX PA99011526A
- Authority
- MX
- Mexico
- Prior art keywords
- hmfg
- individual
- disease
- tumor
- cells
- Prior art date
Links
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Abstract
The present invention provides methods of delaying development of human milk fat globule - (HMFG) tumors using the anti-idiotype antibody 11D10, particularly in high-risk individuals having low tumor burden.
Description
METHODS OF DELAYING THE DEVELOPMENT OF TUMORS ASSOCIATED WITH HMFG USING THE ANTI-IDIOTIDE OF ANTIBODY 11D10
REFERENCES FOUND IN RELATION TO APPLICATIONS.
This application claims the benefits of provisional applications 60 / 049,540, registered on June 13, 1997, which was converted into the US application No. (the serial number was not yet assigned) registered on June 11, 1998.
TECHNICAL FIELD
This invention concerns the uses of the anti-idiotype of antibodies.
REF. 32298 More particularly, it relates to methods of treatment using the 11D10 antibody anti-idiotype, in which the administration of the 11D10 retarder of the development of HMFG-associated tumors.
ANTECEDENTS IN THE SPECIALTY
Despite extensive medical research and numerous advances, cancer remains the second leading cause of death in the United States. Breast cancer is the most common cause of cancer death in women with more than 150,000 new cases diagnosed annually. While traditional modalities of therapy, such as surgery, radiotherapy and chemotherapy, are widely used and are in many cases successful, the still existing high proportion of deaths from cancers such as breast cancer imposes the need for alternative or complementary modalities of therapy. .
Although a patient responds to traditional modalities of therapy, there is often a significant risk of recurrence of the disease. This is especially true if the disease was widespread when it was diagnosed.
Although after "successful" treatment, in which a recovery is observed, a patient may have a high risk of recurrence, and may only "look and wait". There are currently no additional courses of action to delay or prevent recurrence.
One approach to cancer therapy has been immunotherapy. However, human cancer immunotherapy using tumor cells or tumor-derived vaccines has been disappointing for several reasons. It has been consistently difficult to obtain large amounts or antigens associated with purified tumors which are often chemically definitive of the disease and make purification difficult. In addition, in other words, the question of whether a cancer can effectively support an immune response against its (his) or his (her) tumor. Tumor-associated antigens (TAA) are often a part of "themselves" and usually evoke a very poor response in a carrier host tumor due to tolerance to antigens, such as mediating suppression of T cells. with cancer tend to be immunosuppressed and only respond to certain T-dependent antigens.
Immunologists have learned that a poor antigen (in terms of eliciting an immune response) can be converted into a strong antigen by changing the molecular domain.
Changes of hapten transporters allow the auxiliary T cells to become active cells, elaborating the totality of the immune response force. Thus, by changing the carrier, it can also convert a tolerogenic antigen into an effective antigen. McBride et al. (1986) Br. J. Cancer 53: 707. Often the immunological status of a patient with cancer is suppressed in such a way that the patient is only able to respond to certain T-dependent antigens and not to other forms of cancer. antigens. From these considerations, it might make sense to introduce molecular changes in the 'tumor-associated antigen before using them as vaccines. Unfortunately, this is impossible to achieve for most tumor antigens because they are not well defined and are very difficult to purify.
The network of hypotheses by Linder ann ((1973) Ann Im unol.
124: 171-184) and Jerne ((1974) Ann. Immunol. 125: 273-389) offers an elegant approach to transform epitope structures into idiotypic determinants expressed on the. surface of antibodies. According to the network concept, immunization with an antigen associated with a given tumor will generate the production of antibodies against that tumor-associated antigen, called Abl.; this Abl is then used to generate a series of anti-idiotypes of antibodies against Abl, called Ab2. Some of these Ab2 molecules can make effective the three-dimensional mimic structure of the tumor-associated antigen identified by Abl. These particular anti-idiosylls called Ab2ß fit within the Abl paratopes, and express the internal image of the tumor-associated antigen. Ab2ß can induce a specific immune response similar to that induced by the original tumor associated antigen and can therefore be used as a subordinate of tumor-associated antigens. Immunization with Ab2ß can lead to the generation of anti-anti-idiotype antibodies (Ab3) that recognize the aantigen associated with the corresponding original tumor, identified by Abl. Because of this Abl-pprobable reactivity, Ab3 is also called Abl 'to indicate that it is possible to differentiate it from the other Abl idiotypes.
A potentially promising approach to the treatment of cancer is the immunotherapy it employs, anti- biotypes of antibodies. In this form of therapy, an antibody that mimics an epitope of a tumor-associated protein is administered in an effort to stimulate the patient's immune system against the tumor, via the tumor-associated protein. WO 91/11465 describes methods of stimulating an immune response in a human against malignant cells or an infectious agent using anti-idiotypes of primate antibodies. However, not all anti-idiotype antibodies can be used in therapeutic regimens against tumors. First, only a fraction of antibodies produced against an Abl are limited in their reactivity in the Abl paratope (for example, they are non-reactive against features shared with other potential antibodies in the host). Second, anti-idiotype antibodies are not necessarily immunogenic. Third, although an anti-idiotype mimics an immune response, only a fraction of these immunogenic anti-idiotypes manifest an immune response against tumor antigen and not against other antigens with less specificity. Furthermore, since different cancers have molecular and clinical characteristics that vary widely, it has been suggested that anti-idiotype therapy could be evaluated on a case by case basis, in terms of origin of tumors and expressed antigens.
The anti-Id monolonal antibodies that structurally resemble antigens associated with tumors have been used as subtitual antigens in cancer patients. Herlyn et al. (1987) Proc. Nati Acad. Sci. U.S. to. 84: 8055-8059; Mittleman et al. (1992) Proc.
Atl. Acad. Sci. • .A. «89: 466-? r,. r-vh.a-.4t- + t-erjee et al. (1993) ann. N.Y. Acad. Sci. 690: 376-278. All these studies were conducted with patients who had advanced disease. Based on the immune response observed in at least some of the patients, it has been proposed that the Anti-Id provides a partial analogy of the tumor-associated antigen in an isounionic context.
Human milk fat globules (HMFG) are milk fat globules secreted in the lactating breast by epithelial cells of the breast, and are composed of fat droplets coated by plasma membrane.
Likewise, HMFG is a rich source of antigens associated with epithelial membranes. An antigen component of HMFG is a high molecular weight, membrane-associated ucine that is associated with breast cancers or other cancers such as the ovary, lung, and pancreas. Mucin contains a protein with known amino acid sequences derived from the cDNA. Semi-purified HMFG is available in small quantities from several sources and can be used in serological assays. Peterson et al. (1990) Hybridoma 9: 221-235. However, HMFG is extremely difficult to isolate and purify, and purified HMFG is not available for patient immunization or animal studies. Additionally, since some of the epitopes on HMFG are shared with normal tissues, specifically by non-penetrating glycoproteins, immunization with the intact HMFG molecule possibly causes potentially damaging autoimmune reactions. An immune reaction against an epitope associated with tumor, on the other hand, would be much more desirable.
A series of murine monoclonal antibodies (mAbs) that recognize the components of HMFG have been described as being primarily associated with human breast carcinomas and not with mostly normal tissues. Chatterjee et al.
(1993) Ann. N.Y. Acad. Sci. 690: 376-377; Ceriani et al. (1983) Somatic Cell Genet. 9: 415-427. Among these mAbs, MC-10 (BrE-1) is the most restricted and specific, which reacts with mucin-like proteins of a high molecular weight (Molecular Weight, 400,000) present in high density and above > 80% in breast cancer cells and minimally expressed on a few normal tissues, such as the lung epithelial line and kidney tubules. Ceriani et al. (1983); Ceriani and collaborators
(1990) Antibody Immunoconjugates and Radiopharmaceuticals 3: 181-198.
Recurrent breast cancer is not curable by standard therapies. Consequently, new therapeutic approaches for this disease are necessary. Although a patient responds to traditional therapy, there is often a significant risk of recurrence. Therefore, new therapeutic approaches for this disease. They are necessary. The present invention overcomes deficiencies in the prior art by providing an anti-idiotype of monoclonal antibody (11D10) as an antigen (Ag) that induces an immune response against HMFG.
All references cited in the presnete are incorporated as a reference in their entirety.
DESCRIPTION OF THE INVENTION
The present invention is directed towards therapeutic uses of the 11D10 antibody anti-idiotype.
Accordingly, an aspect of the invention are methods of delaying the development of tumors associated with HMFG in an individual having a low-weight tumor, particularly high-risk individuals. These methods include the administration of an effective amount of the 11D10 antibody anti-idiotype to the individual. In another aspect, the invention additionally includes the administration of 11D10 with an adjuvant.
In another aspect, methods are provided for the treatment of a HMFG-associated tumor in an individual with a low-weight tumor that includes. administer an effective amount of ~ 11D10 to the individual.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 represents the cDNA sequence (SEQ ID NO: 1) and the amino acid sequence (SEQ ID NO: 2) of the light chain variable region of 11D10 and the attached residues. The CDRs and structural regions are indicated.
Figure 2 represents the cDNA sequence (SEQ ID NO: 3); and the amino acid sequence (SEQ ID NO: 4) of the heavy chain variable region of. 11D10 and accompanying waste. The CDRs and structural regions are indicated.
Figures 3A and B represent the amino acid sequences of the CDRs and structural regions of the light chain (Fig. 3A) and heavy chain variable regions (Fig. 3B) of 11D10.
MODALITIES FOR CARRYING OUT THE INVENTION
This invention is based on the ability of 11D10 to generate a specific HMFG immune response in patients who are at high risk of recurrence of associated HMFG diseases. We believe that the administration of 11D10 can reduce the risk of the occurrence of HMF-associated tumors, particularly in high-risk individuals in the adjuvant setting.
11D10 is an anti-idiotype (Id) of murine antibody (Ab2) that induces a specific immune response against a distinct and specific epitope of human milk fat globules (HMFG), a tumor-associated antigen. The generation and characterization of 11D10 as well as the DNA sequences encoding the variable regions of 11D10 (light and heavy chains) have been commonly described in our patent applications no. 08 / 766,350 (authorized official number 30414/2000321). A hybrid that produces 11D10 has been deposited with American Type Culture Collection
(ATCC), 12301 Par la n Drive, Rockville, MD, USA. 20852 on January 17, 1996 under the provisions of the Treaty of
Budapest for the International Recognition of Deposits of Microorganisms for the Purposes of Patent Procedures. Accession number HB12020 was granted.
In a Phase I, after clinical trials, 12 patients who had disease associated with advanced HMFG in the breast
(who had failed all previous therapies and still had high-weight tumors) were administered with 11D10.
Chakraborty et al. (1997) Proc. Am. Ass. Cancer
Research: 4139. Five of the twelve patients generated significant levels of specific antibodies against anti-Id (Ab3) that were able to inhibit the binding of Ab2 to Ab2 and vice versa. This is especially significant, how many of these patients, either because of the nature of their previous treatment or their illness or both, they are moderately or severely compromised, and they often received 11D10 as a final option. The affinity of purified Ab3 from serum of 3 patients specifically associated with the purified HMFG antigen and immunoblotting of breast cancer tissue sections. The antibody isotype (Ab3 / Abl ') was predominantly IgG. Peripheral blood lymphocytes (PBL) isolated from 3/12 immunized patients showed in vitro proliferative responses of T-cell specific idiotype. The results suggest that anti-ID 11D10 can induce both humoral and cellular immune responses in some patients with advanced cancer. breast who were strongly pretreated. The toxicity was minimal with only slight erythema and induration at the site of injection. However, all these patients exhibited a normal progression of the disease.
Definitions
As used herein, the terms "11D10", "11D10 antibody" and "anti-idiotype monoclonal antibody 11D10" are used interchangeably to refer to an anti-idiotype of an antibody (Ab2) that contains an epitope that at least Partially it seems a distinct and specific epitope of human milk fat globules (HMFG) first expressed in human breast tumor cells. The generation and characterization of 11D10 is commonly described in our patent applications no. 08 / 766,350. See also Mukerjee et al. (1992) FASEB J. A2059 (Abs.6505); Murkerjee et al. (1992) FASEB J. A12713 (Abs.7792); Charaborty et al. (1994) Proc. Am. Assoc. For Cancer Res- 35: 2963; Chacraborty et al.
(1995) Cancer Res. 55: 1525-1530; Bhattacharya-Chatterjee et al. (1994) Antigen and Antibody Mole. Eng. Breast
Cancer Diagnosis and Treatment, (Ceriani, ed.) 139-148.
Different biological functions are associated with 11D10, which include but are not limited to, binding to Abl (MC-10) and / or Ab3 and an ability to induce an immune response (humoral and / or cellular) against HMFG in mice, rabbits, monkeys, and humans advanced HMFG-associated disease, particularly associated HMFG tumors, as well as humans with a history of disease associated with HMFG but not detectable disease.
"HMFG" is an abbreviation for fat globules in human milk. HMFG has several proteinaceous (and therefore antigenic) components. As used herein, it refers to a semipurified extract of a HMFG-expressing breast cancer cell line, prepared as per the method of Ceriani et al. (1977) Proc. Acad. Sci. USA 74: 582-586), together with related antigenic substances, including HMFG expressed on breast cancer cells and more highly purified preparations. Contained in HMFG is a high molecular weight mucin of known amino acid sequence, an epitope that is recognized by the monoclonal antibody MC = 10 used as Abl in 11D10 cultures. Accordingly, the immunological reactivity antiAHMFG induced by immunizing an animal with 11D10 preferably binds a polypeptide epitope or a related determinant antigen to be recognized by MC-10.
MC-10 was selected for anti-Id production because it defines a unique and specific epitope of a high molecular weight mucin of human milk fat globule (HMFG), first expressed in high density in human breast cancer and some other tumor cells but was not found on normal adult tissues by spotting immunoperoxidase, or hematopoietic cells that include granulocytes by cytometric flow analysis. MC-10 (also called BrEl) is quite restricted and specific in the sense that it reacts with a large molecular weight mucin (Molecular Weight 400,000) present in only a minute amount in human mammary epithelial cells and increased by at least 10 times on breast carcinoma cells. WO 8907268; EP 401247. The antibody is cytotoxid for breast cancer cells in in vitro studies. Ceriani et al. (1983); Peterson et al. (1990). MC-10 has a very restricted histopathological distribution in normal tissues. MC-10 only links some areas of the epithelial line of the lung and scattered distal spiral tubules of the kidney, with an inapparent histopathology that links normal breast tissues and many other normal epithelia (colon, pancreas, stomach, thyroid, bladder, liver). ) and other normal tissues (adrenal, brain, lymph nodes, myocardium, ovary, spleen, testes). On the other hand, a high percentage of different human tumors, including breast, endometrium, lung, ovary, and pancreas bind to mAb MC-10 intensely. Formalin-fixed tumors studied by binding MC-10 (positive number / total number) includes: breast carcinoma (CA) (144/182), CA colon (3/27), CA duodenum (0/1), CA endometrium (7/14), CA ribon (0/11), CA pilon (41/47), CA ovary (20/26), pancreas CA (9/15), prostate CA (0/2), salivary glands CA (0/3), stomach CA (2/7), thyroid CA (0/7), hepatocolangio CA (8/33), cell of islet CA (0/2), lymphoma (0/20), melano a (0/23), eningioma (0/5), Merkel cell (4/9), mesothelium a (1/11), neuroblastoma ( 0/2), oncocytoma (1/1), paraganglioma (0/10), Pleodeno a (0/7), among sarcomas: unclassified (0/1), alveolar (0/1), angiosarcoma (0 / 1), clear cells (0/2), cystosarcoma (0/1), epithelioid (5/12), Eing (0/1), fibrosarcoma (0/1), leiomyome (0/2), liposarcoma ( 0/1), fibrohistiocyte to malignant (0/2), synovial mesotlioma (0/7), CA elongated cells (5/16), undifferentiated (1/9); scíiwannoma (0/3), seminoma (0/4), teratoma (0/3), thymoma (0/8), transient CA (5/10), undifferentiated CA (7/29), tumor of Warthin (0) / 1), Ceriani et al. (1990). We also studied hematopoietic cells for the presence of MC-10 antigen by FACS analysis in our laboratory and found the cells, which include granulocytes and platelets, negative for the antigen. Positive control of MCF-7 cells stained strongly with MC-10.
A "HMFG-associated tumor" is one that contains a HMFG antigen, especially expressed on the tumor cell surface, that binds to MC-10 (Abl). As previously observed, this antigen is found on a wide variety of tumors, particularly breast cancer (about 90% of patients with breast cancer had tumors that reacted with MC-10). Therefore, 11D10 has the potential to be used in a wide variety of cancers in which HMFG is detected. Methods of detecting HMFG are known in the art and examples are described herein.
Co or used in the present "treatment" is an attempt to obtain beneficial or desired results.
For purposes of this invention, beneficial or desired results include, but are not limited to, one or more of the following: relief of symptoms, decrease in the extent of the disease, stabilized state (eg, not worsening) of the disease, prevent the spread, (for example, metastasis) of the disease, prevent the recurrence or occurrence of the disease, slow or slow the progress of the disease, improve the disease state, and recovery (either partial or total). Also encompassed in "treatment" is a reduction in the pathological consequences of a HMFG-associated tumor.
As used herein, "retarding" the development of a HMFG-associated tumor means deferring, preventing, slowing down, retarding, stabilizing, and / or postponing the development of the disease. This delay can be of several extensions of time, depending on the history of the disease and / or individual being treated. As is clear to the expert in the matter, a sufficient or significant delay can, in effect, encompass prevention, in which individuals do not develop the disease. A method that "retards" the development of HMFG-associated tumors is a method that reduces the likelihood of developing the disease in a given time frame and / or reduces the extent of the disease in a given time frame, when compared to Do not use the method. Such comparisons are typically based on clinical studies, which use a statistically significant number of subjects.
"Development" of HMFG-associated tumors means the progress of tumors. The development of the tumor may be detectable using standard clinical techniques as described herein. However, development also refers to the progress of the disease that may be undetectable. For purposes of this invention, progress refers to the biological course of the disease state, in this case (eg, HMFG-associated tumors) cell division and / or tumor metastasis-HMFg-associated. "Development" includes occurrence, recurrence, and onslaught. As used in the present "assault" or "occurrence" of HMFG-associated disease includes initial attack and / or recurrence.
As used in the present "low-weight tumor" it means that an individual does not have advanced HMFG-associated tumor. "Advanced" HMFG-associated tumor means that there are detectable metastases, which are, tumor masses detectable in other sites than the primary site of the tumor. Tumor masses are generally detected by imaging techniques known in the art such as X-rays, CT scans, or MRI scans, as well as imaging and diagnostic techniques that detect masses of tumors that could be detected by X-rays. , CT scan, or MRI. As used herein, "advanced" disease does not include involving lymph nodes. It is understood that "low-weight tumors" also includes non-detectable tumors using conventional diagnostic techniques such as X-ray, CT scan, or MRI. Preferably, an individual with a low-weight tumor has been evaluated as having stage III, preferably stage II, also more preferable stage I of the disease. As described below, also preferable is a disease that has been treated by surgery, radiation and / or chemotherapy and is not largely detectable by conventional diagnostic techniques and / or imaging. As yet preferred examples, individuals with low "low-weight tumor" also include those who have surgical resection of the primary tumor whose disease is not detectable or some remnant of the disease due to, for example, inability to resect any detectable disease, or less extensive disease. Other examples of low-weight tumor categories are provided below.
As used in the presnete, a "high risk" individual is an individual who has a higher risk of developing HMFG-associated tumors. A "high risk" individual may have no detectable disease, and may or may not have had detectable disease prior to the treatment method described herein. "High risk" denotes that an individual has one or more of the so-called risk factors, which are measurable parameters that correlate with the development of HMFG-associated tumors.
An individual who has one or more of these risk factors is more likely to develop HMFG-associated tumors than an individual without these risk factors. These risk factors include, but are not limited to, age, sex, race, diet, history of previous diseases, presence of disease precursors, genetic considerations (eg hereditary), and environmental exposure. Examples (eg categories) of high-risk groups are discussed below. Depending on the basis and context of the high-risk assessment, the time frame in which the probability of disease or tumor development, progress, and / or onslaught would be more likely to not vary. For example, with breast cancer, high-risk patients in the adjuvant setting, the risk of occurrence is typically measured in one to five years. For patients with non-small cell lung cancer in an adjuvant setting, the risk of occurrence is typically measured in one to two years. For patients with precursor disease, the risk of occurrence can be measured in a longer time frame. For an individual that is considered high risk due to, for example, genetic or hereditary considerations, the risk of occurrence can be measured in an equal time frame, which includes the expected life time of the individual.
An individual with "low risk" is one that is not considered "high risk".
"Adjuvant framework" refers to an allocation in which an individual has had a history of HMFG-associated disease, particularly HMFG-associated tumors, and has responded to therapy. Prior therapy may be included, but is not limited to, surgical resection, radiation therapy, and chemotherapy. As a result of this prior therapy, these individuals do not have clinically edible tumors as well as detected by conventional diagnostic techniques such as X-ray, CT scan, or MRI, or techniques that detect tumors detectable by X-ray, CT or MRI scanning. However, because of their history of HMFG-associated disease, these individuals are considered at risk of developing the disease. The treatment or administration in the "adjuvant framework" refers to a subsequent treatment modality. The degree of risk (for example, whether an individual in the allocation of the adjuvant is considered "high risk" or "low risk") depends on several factors, more usually the extent of the disease at the time of the first treatment.
As used in the present "adjuvant framework" it is differentiated from an "adjuvant", which refers to a chemical or biological agent in a pharmaceutical preparation in combination with an agent (such as an antibody, polynucleotide or polypeptide) to improve its immunogenicity. Examples of adjuvants are described herein.
A "neo-adjuvant framework" refers to the period after diagnosis but before the initiation of treatment modalities other than the administration of 11D10. For example, if an individual is diagnosed as having a HMFG-associated tumor, such as in breast, for which the surgery is indicated, administration of 11D10 is neo-adjuvant framework means that the administration of 11D10 begins before the surgery.
An "effective amount" is an amount sufficient to result in beneficial effects or desired results, preferably in a clinical context. An effective amount can be administered in one or more administrations. For purposes of this invention, an effective amount of 11D10 is an amount of 11D10 that is sufficient to improve, stabilize, or retard the development of the stages of HMFG-associated disease, particularly HMFG-associated tumors. The detection and measurement of these efficiency indicators are discussed below.
An "individual" is a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, farm animals, sport animals, and pets.
Modalities of the Invention
In one embodiment the invention provides methods for delaying the development of a HMFG-associated tumor in which an effective amount of 11D10 is administered to an individual having a low-weight tumor. Examples of HMFG-associated tumors include, but are not limited to, carcinoma of the breast, carcinoma of the ovary, non-small cell carcinoma of the lung, and pancreatic carcinoma. Methods of detecting HMFG-associated tumors are known in the art, including standard immunoassays and / or imaging techniques. As an example, HMFG-associated tumors can be detected by immunohistological examination of the affected tissues, using, for example, MC-10 as the primary antibody in an indirect immunoflusion test, FACS analysis, or immunoperoxidase spotting test.
In one embodiment, the invention encompasses the administration of 11D10 to a high-risk individual who has a low-weight tumor. As discussed above, a high-risk individual presents one or more of the risk factors that correlate with the development of the HMFG-associated tumor. All (for example, increased) risk can be indicated, for example, on the basis of a genotype of the individual (for example, the presence of a gene or mutation that is associated with the development of HMFG-associated tumors, increased expression of genes associated with tumors or decreased expression of tumor suppressor genes, presence of precursor disease (such as noninvasive masses), a family history of HMFG-associated cancer, a history of exposure to an environmental substance or form of radiation that is known or suspected of being carcinsgéncia or teratogénica (particularly suspicious of causing HMFG-associated tumors), exposure to other types of cancers of other types of irregular or abnormal development of tissues.Also included as high risk are individuals suspected of having a positive HMFG tumor based on a test positive for anti-HMFG immunological reactivity Such individuals include those who may have had their primary tumor surgically removed and are at high risk because of the size of the primary tumor or the presence of positive lymph nodes.
Because all the risk factors for developing HMFG-associated tumors are not known, and the interplay between these factors (in terms of total risk) are not fully understood, it is clear to one skilled in the art that appropriate individuals for administration of 11D10 for purposes of the invention may have characteristics in common, and that individuals who do not fall clearly into the categories described above can in no way be considered suitable candidates for the administration of 11D10. An expert clinician can make an empirical determination of whether an individual is suitable for 11D10 treatment. For example, an individual with a family history (for example genetic) of breast cancer could be considered "high risk", even if no previous disease has been observed in this individual. In this context, the administration of 11D10 to an individual could result in a delay in the occurrence of the disease, to the extent that the individual does not develop the disease in his (or her) life (or time). develops it later than might be expected). Another example is an individual who is being treated using traditional modalities of therapy, and has been shown to be more responsible for the therapy (eg, recovery). Such an individual may be adjudged as "high risk", equally though the course of therapy is not yet completed, due to the projection of progress by the administration of the therapy, and may be a suitable candidate to receive 11D10 before of the term of the initial therapy- The discretion to determine if the treatment using 11D10 can be indicated is that of the person responsible for the therapy.
It is also evident that the administration of 11D10 can also be indicated if an individual is not considered to be at high risk (for example, it is "low risk") according to the criterion of concurrent risk assessment. For example, an individual who has been successfully treated and is not considered high risk (due, for example, to the lack of invasive disease detectable at the time of diagnosis) can in no way be a candidate to receive 11D10 as a precautionary measure, especially considering the lack of contraindications and the lack of undesirable side effects so far observed in 11D10. Therefore, the risk of progression of the disease can also be further decreased by administration of 11D10. As another example, an individual may believe that he or she is at risk of developing the disease, and may decide that receiving 11D10 could reduce this risk. Also suitable are individuals with supernormal levels of HMFG expression. The expression levels of HMFG can be determined, for example, by immunohistological examination of the affected tissue, using for example, MC-10 as the primary antibody in an indirect immunofluorescence test.
In another embodiment of the present invention, 11D10 is administered to a high-risk individual in the adjuvant assignment. Typical factors indicating high-risk frame adjuvant individuals are invasion by the tumor in the vicinity of the tissues (eg, extensive disease), and / or loping the lymph nodes. Examples of high-risk individuals in the adjuvant setting include, but are not limited to, (a) patients with stage II or stage III non-small lung cancer (NSCLC) who have had their tumor resected but have positive node region lymphatics (these patients have a 60-80% chance of relapse in the first 2 years); and (b) breast cancer patients having positive lymph nodes in preferably at least 5, more preferably at least 10 positive lymph nodes (70-80% chances of relapse in the first 2 years for those with at least 10 lymph nodes) positive). Another example of a high risk individual in adjuvant setting is an individual having ovarian cancer who is an HMFG-associated tumor and has detectable post-surgical disease. This detectable post-surgical disease, generally due to non-intersecting disease, is generally visually detectable (for example, when a patient is in surgery), although its presence may be based on other detection methods, such as CT scanning. In another embodiment, 11D10 is administered in a neo-adjuvate assignment. It is understood that, for purposes of this invention, an individual in a neoadjuvant setting has a low weight tumor. Preferably, when administered in the neo-adjuvant setting, an individual having a low-weight tumor.
Another example of an individual suitable for 11D10 therapy as described in this invention is an individual with a low-weight tumor. Accordingly, the present invention encompasses methods for treating HMFg-associated tumors in an individual having a low-weight tumor comprising administering an effective amount of HMFG, as defined above, a "low" weight tumor means that the disease does not It is considered advanced. For example, a low-weight tumor may be the disease in full or partial recovery as considered by a clinical practitioner. Tumor of "low" weight can also be induced by a reduction in tumor weight in advanced disease so that the extent of the disease is not considered to be advanced. Other examples of low-weight tumor include contained disease to limit involvement of the lymph nodes. An individual with a low-weight tumor can be further classified as "high risk" or "low risk", depending on the individual history of the disease and treatment. As one skilled in the art could readily appreciate, an individual with a low-weight tumor could be treated in the non-adjuvant, neo-adjuvant, and / or adjuvant settings.
The invention also includes methods of treatment using 11D10 for individuals having residual disease, particularly minimal residual disease. "Residual" disease is any HDlO-associated disease, particularly HMFG-associated tumors that remain after therapy but that are not detectable by conventional diagnostic techniques such as X-rays, CT or MRI scans, or techniques that detect tumors detectable by X-ray. , CT scan, or MRI. Accordingly, "residual disease" refers to the probable presence of disease that may develop into detectable disease, and refers to a prognosis and / or assumption made in an adjuvant picture. Depending on the type of HMFG-associated tumor and, for example, the extent of the disease in diagnosis, an individual may be considered to have residual disease, although equally undetectable disease is present. For example, an individual with resectable NSCLC has residual disease after surgery (eg, resection), even if an apparent full recovery takes place. Similarly, an individual with breast cancer may have residual micrometastatic disease after chemotherapy. Alternatively, an individual who is currently undergoing therapy for an HMFG-assigned tumor also has "residual" disease. It is understood that, as used herein, "residual" disease does not include advanced disease. "Residual" disease and "minimal residual" disease as used herein are both not detectable using conventional diagnostic techniques such as X-ray, CT scan, or MRI, or techniques that detect tumors detectable by X-rays, CT or MR scans. .I, but refers to extension or varying degrees of the disease.
The invention also encompasses methods of reducing the risk of occurrence of HMFG-associated disease, particularly HMFG-associated tumors. In these methods, an effective amount of 11D10 is administered to an individual at risk of developing HMFG-associated disease. "Reduce the risk of occurrence", means that the risk of occurrence and / or recurrence of HMFG-associated disease is lower in individuals who receive 11D10 than in those individuals (who have the same risk of occurrence) who do not receive it. An individual "at risk" of developing HMFG-associated disease may have high risk or low risk, depending on the clinical and genetic history and the status of the individual.
In another embodiment, the invention provides methods of treating a. HMFG-associated tumor, particularly breast cancer, which ~ includes administration of certain chemotherapeutic agents and 11D10. We believe that certain chemotherapeutic agents can act synergistically with 11D10 to improve the immune response. Suitable chemotherapeutic agents can be determined based on data indicating that the chemotherapeutic agent can stimulate the immune response, or not decrease the immune response. Methods of measuring the immune response are known in the art and are described herein. The administration of these chemotherapeutic agents is generally still accepted in clinical protocols.
For all the above-described embodiments of the present invention, 11D10 can be prepared, administered, and monitored as described in the following sections.
Preparation and Administration of Anti-idiotype of 11D10 antibody All embodiments of this invention are linked to the administration of an effective amount of 11D10.
11D10 can be obtained in several ways. For example, 11D10 may be produced from the ATCC hybridoma No. HB 12020 described herein. Methods of antibody isolation are well known in the art. See for example, Harlow and Lane (1988) Antibodies: A Laboratory Manual, Cold spring Harbor Laboratory, New York, and sambrook et al. (1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory. The antibody can be obtained from the hybridoma via tissue culture or from mouse ascites. These techniques are known in the art. For example, the cells can be cultured in a suitable medium, and the culture medium can be used as a source of antibodies. Optionally, matrix-coated channels or beads and co-cultured cells can be included to enhance the growth of the antibody-producing cells. For the production of large quantities of antibody, it is generally more convenient to obtain ascites in fluid. Such methods are known in the art, and generally comprise injecting the hybridoma cells into a naively immunologically histocompatible or immunotolerant mammal, especially a mouse. The mammal is optionally first-time for the production of ascites by prior administration of a suitable composition; for example, Pristane. Preferably, 11D10 is purified from BALB / c ascites using recombinant protein chromatography G-agarose, followed by Protein -A-Cl-sepharose 4B chromatography.
Alternatively, 11D10 can be chemically synthesized using techniques known in the art, for example, using a commercially available automated peptide synthesizer such as that manufactured by
Applied Biosystems, Inc. (Foster City, CA).
11D10 can also be obtained by use of routine recombinant methods such as those described in Sambrrok et al. (1989). For example, a polynucleotide that encodes either heavy or light 11D10 can be cloned into a suitable expression vector (containing control sequences for transcription, such as a promoter.) The expression vector is itself introduced into a cell Guest. The host cell is developed under suitable conditions such that the polynucleotide is transcribed and transferred to a protein. The lOdll of heavy and light chains can be produced separately, and then combined by rearrangement of the disulfide bond. Alternatively, vectors with separate polynucleotides encoding each strand of 10D11, or a vector with a single polynucleotide that encodes both separate co or transcribed strands, can be transfected into a single host cell which can then produce and assemble the entire molecule. Preferably, the host cell is a larger eukaryotic cell that can provide the normal carbohydrate complement of the molecule. 11D10 thus produced in the host cell can be purified using standard techniques in the art.
A polynucleotide encoding 11D10 for use in the production of 11D10 by any of these methods can in turn be obtained from the hybridoma that produces 11D10, or be produced synthetically or recombinantly from the DNA sequences described in patent applications commonly owned by us. us. 08 / 766,350 (authorized official No. 30414/2000321) using standard techniques in the field. Figure 1 shows the light chain variable region cDNA sequence of 11D10 (SEQ ID NO: 1); Figure 2 shows the heavy chain variable region cDNA sequence of 11D10 (SEQ ID NO: 3). The total sequences of light and heavy chain constant regions of 11D10 have not been determined, but are expected to be identical or substantially identical to those of other mouse immunoglogulin molecules. For the mouse kappa light chain constant chain, four genetic allotypes encoding two protein allotypes have been published by Solin et al. (1993) Immunogenetics 37: 401-407, which is therefore incorporated herein by reference. Figure 1 of Solin et al. Presents the mouse and rat immunoglobulin kappa chain gene sequences, comparing the sequences in the kappa chain constant region for different strains and high lightness allotypic differences. The sequences of constant kappa chain regions are included for BALB / c, PL, SJL, and M spretus. Other allotypes that are naturally found are possible. The mouse heavy chain constant region DNA sequence from neonatal mice has been published by Honjo and coalboradores (1979) Cell 18: 559-568, which is therefore incorporated herein by reference. Figure 5 of Honjo shows the germ line Dna sequence, together with the encoded protein sequence. It shows in the line above another protein sequence obtained from the mouse myopoma MOPC 21. Other allotypes that are naturally found are possible. Polynucleotides encoding 11D10 can also be derived from amino acid sequences of 11D10, the variable regions of which are given in Figure 1 (light chain; SEQ ID NO: 2) and Figure 2 (heavy chain; SEQ ID NO: 4) ). Of the given 11D10 amino acid sequence, one skilled in the art can designate polynucleotides encoding 11D10.
The 11D10 antibody isolated from the ATCC hybridoma no. HB 12020 is from the mouse IgGl subclass, and can be isolated by any suitable technique for immunoglobulins of this isotype. Purification methods may include precipitation salts (for example, with ammonium sulfate), ion exchange chromatography (for example, anion exchange column run at neutral pH and eluted with gradient steps of ionic strength increase), gel filtration (which includes HPLC gel filtration), and affinity chromatography on resins such as protein A, protein G, hydroxyapatite and anti-immunoglobulin. 11D10 can also be purified on affinity columns comprising paratope MC-10 (BrEl); for example, in the form of a purified Abl or Ab3.If 11D10 is administered to an individual, 11D10 is preferably at least 80% pure, more preferably at least 90% pure, equally more preferably at least 95%, equally more preferably at least 98%, as well as also free of pyrogens and other pollutants In this context the percent purity is calculated as one percent by weight of the total protein content of the preparation. An 11D10 preparation for immunization is described in Example 1.
Preferably, 11D10 is administered with a pharmaceutically acceptable excipient. A pharmaceutically acceptable excipient is a relatively inert substance that facilitates the administration of a pharmacologically effective substance. For example, an excipient can give shape or consistency to the composition of the vaccine, or act as a diluent. Suitable excipients include but are not limited to stabilizing agents, wetting agents and emulsifiers, salts for varying osmolarity, encapsulating agents, regulators, and skin penetration enhancers. Examples of pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences (Alfonso R. Gennaro, ed. 18 th edition, 1990).
Preferably, 11D10 is used with an adjuvant that improves preparations of 11D10 or otherwise enhancers of the immune response against 11D10. Aerated adjuvants include aluminum hydroxide, alumina, QS-21
(US Patent No. 5,057,540), DHEA (US Patent Nos. 5,407,684 and 5,077,284) and its derivatives (including salts) and precursors (for example, DHEA-S) beta-2-microglobulin (WO 91/16924) , muramyl dipeptides, muramyl tripeptides (US Patent No. 5,171,568) Monophosphoryl lipid (US Patent No. 4,726,947). Other suitable adjuvants include but are not limited to aluminum salts, mixtures of squalene (SAF-1), muramyl peptide, saponin derivatives, mycobacterium block preparations, icolic acid derivatives, blocks of non-ionic surfactant copolymers, Quil A, cholera toxin B subunit, polyphosphazenes and drivates, and immunostimulatory complexes (ISCOMs) such as those described by Takaahashi et al. (1990) Nature 344: 873-875. For veterinary use and for production of antibodies in animals, mitogenic components of Freund's adjuvants can be used. The selection of an adjuvant will depend in part on the stability of the vaccine in the presence of the adjuvant, the route of administration, and the regulatory acceptability of the adjuvant, particularly when prescribed for human use. For example, alumina is provided by the Unites States Food and Drugs Administration (FDA) to be used as an adjuvant in humans. Preferably, 11D10 alumina-precipitate is used. The preparation of precipitated aluminum hydroxide 11D10 is described in Example 1. preferably, QS-21, Acquila Biotech, Worcester, MA) or DET0X ™ PC (Ribi Im unochem, Hamilton, MT) is used.
STMULON ™ QS21, available from Acquila Biotech (formally Cambridge Biotech Corp.), Worcester, MA, is a component of the extract of the Quillaja saponaria Molina tree. The molecule of QS-21 (C92H148046, Molecular Weight, 1990) consisted of triterpene glucoside with the genreaal structure of a qqaic acid 3, 2888-O-his glycoside. It consists of two isomer structures designated VI and V2 in a typical ratio of VI: V2 of approximately 2: 1. Preferably, 100 g of STIMULON ™ QS-21 is used by administration of 11D110.
DETOX ™ PC, commercially available from Ribi Immuno iochem (Hamilton, MT) is a mixture of skeletal wall cells (CWS) from Micobacterium phlei and Monophosphoryl Lipid A (MPL®) from Salmonnella minnesota Re595 prepared as a stable oil-in-water emulsion with squalane, salt Tween 80, egg phosphatidylcholine and α-tocopherol. The ratio of CWS to DETOX ™ PC in DET0X ™ PC is 10: 1 by weight. Each vial contains 300 μg of CWS, 30 μg of MPL®, 4.5 mg of squalane, 0.6 mg of TWEEN 80, 1.8 mg of egg phosphatidylcholine and 60 μg of α-tocopherol.
The storage recommendations of the DET0X ™ PC is 2-8 ° C, and sterile water water is used as a diluent.
Preferably, 250 μg of CWS and 25 g of MPL® are used per administration.
11D10 can be used in conjunction with other immunomodulators, such as, for example, interleukin 1 (IL-2), IL-4, IL-3, IL-12, GM-CSF, G-CSF, interferon and "keyhole limpet hemocyanin" "(KLH).
11D10 can also be used in conjunction with other agents that serve to improve and / or complement the effectiveness of 11D10. Examples of such agents include, but are not limited to, peptides derived from HMFG or 11D10. The preferred HMFG and 11D10 peptides are those based on the homology between 11D10 and HMFG.
Alternatively, 11D10 can be encapsulated in liposomes. Liposomes suitable for packaging polypeptides for cell delivery are known in the art.
The 11D10 can be heat treated before administration and the heat treatment can be in the presence of the adjuvant, for example, alumina. If QS-21 is used, then the Ig portion of the adjuvant can be heated. Generally, DET0X ™ PC is not heated. For example, 11D100 can be heated to about 40 ° to 80 ° C, preferably 45 ° C, for a period of about 5 minutes to 2 hours, preferably 15 minutes to 1 hour. The heat treatment is preferably up to 45 ° C for 30 minutes in a sterile vial in a water bath. The heat treatment can sometimes take place before administration. Preferably, the heat treatment is in 7 days of administration. Other thermal treatment procedures may be used, as long as the desired activity of 11D10 is not significantly compromised. The heat treated 11D10 is administered as described herein.
For treatment using 11D10, an effective amount of 11D10 is administered to an individual parenterally, preferably intracutaneously. Other routes of administration include, but are not limited to, intramuscular, intradermal. If 11D10 precipitated alumina (or aluminum hydroxide) is used, 11D10 is preferably administered intracutaneously. If QS-21 or D? T0X ™ PC is used, 11D10 is preferably administered subcutaneously. Depending on the particular adjuvant used, a manufacturer may provide suggested routes of administration as well as suggested amounts of adjuvants to be used. 11D10 can also be administered indirectly, by treatment of cultured cells followed by introduction of these cultured cells into an individual. The routes of administration may also vary during the course of treatment. For example, an individual may receive 11D10 intravenously followed by intraperitoneal administration.
The amount of 11D10 given to the individual will depend on several factors, such as the individual's condition, the individual's weight, the nature of the disorder or disease being treated, the extent of the disease, the route of administration, how much dose will be administered, and the desired objective. Preferably, the dose per administration will be in the range of about 10 μg to 20 mg, preferably 200 μg to 15 mg, more preferably 500 μg to 10 'mg. also more preferably 1 mg to about 4 mg, likewise more preferably 2 mg. Preferably, the dose is 2 mg of precipitated 11D10 alumina, 2 mg of 11D10 with QS-21 or 2 mg of 11D10 with DET0X ™ PC.
The interval between administrations of 11D10 may vary and will depend on the disorder being treated and the response of the individual. 11D10 is preferably administered first as a priming dose followed by at least one, preferably two, more preferably three, booster doses. Additional reinforcement doses can be given to improve or renew the response over a base period. 11D10 can be administered on a weekly basis, preferably bisexual, until a desired measurable parameter is detected, such as the manifestation of an immune response. The administration may be continued on a less frequent basis, such as bi-annually or monthly as appropriate. The distribution of subsequent injections (eg, maintenance dose) will depend, inter alia, on the condition and response of the individual being treated. Levels of Ab3 can be monitored, preferably by diagnostic methods described herein, to determine when maintenance (reinforcement) administrations could be given, which could generally be approximately every two or three months. In one modality, the initial series of administrations is given at biweekly intervals for a total of four injections, followed by monthly injections.
It is understood that for some situations the individual receiving 11D10 may be moderately swallowed up to severely immunocompromised, either due to the nature of price treatments, the disease itself, or both. Accordingly, the time required to achieve an immune response and / or the number of injections of 11D10 and / or the amount of 11D10 per administration may vary. For example, an individual may require a longer time to manifest an immune response once 11D10 has been administered. In this case, it is recommended that the individual be monitored for an immune response, even if an initial immune response has not been detected. As another example, an individual may require more than the average number of injections to manifest an immune response. Alternatively, it may be desirable to have the intervals between injections more extensive than monthly, for example, in order to optimize the immune response, such as a T cell response. To reach an immune response, it is considered to be at least partially indicative, preferably fully indicative, of the effectiveness of 11D10 in terms of obtaining beneficial or desired results and therefore can be a useful indicator of effective 11D10 determinant quantities.
A possible indication of the effectiveness of administration of 11D10 or if the administrations of 11D10 are indicated, is the density of HMFG in the tumor cells. This density can vary widely from individual to individual, and can vary during the course of 11D10 administration and / or during the course of the disease. As used herein, "density" of HMFG may refer to either or both of the following: (a) the number of cells per total cells in a given biological sample having HMFG on its surface; (b) the amount of HMFG on the surface of each cell. The density (a) is calculated by looking at the number of cells in a sample that are stained or otherwise indicating that HMFG is present divided by the total number of cells. This density could preferably be greater than about 20%, more preferably greater than 30%, more preferably greater than about 50%, more preferably more than 70%, more preferably more than 80%, more preferably more than 90%. Accordingly, the invention includes the administration of HMFG to an individual having a HMFG density greater than about 20, preferably greater than 30%, more preferably greater than 70%, likewise more preferably greater than 80%, more preferably greater than 90% .
The dendity (b) is indicated by the relative intensity of spotting (or intensity of any measurement indicating the presence of HMFG) of cells in a sample of an individual in relation to, for example, a sample of another individual.
For this density, a person skilled in the art can make an empirical determination of density. The density (b) is relative to normal tissues (e.g. cells lacking HMFG, or unaffected cells), preferred ranges may have approximately 1.5 times preferably 3 times, more preferably about 10 times higher expression on unaffected cells, as detected by immunohistochemical staining density. Unaffected cells could also be from the same individual.
This does not mean that individuals with lower densities, for example, less than about 50%, are not indicated for 11D10 administration. Since it is not desirable to be limited by a single theory, it is possible that the administration of 11D10 could reveal a series of immunoreactions as a result of a general response that is effective against a HMFG-associated tumor, such as a T cell response. cytotoxic A lower density, however, may indicate that additional therapies are desirable.
It is understood that density can also be used as an indicator of disease spread and response to 11D10 administration. For example, a sample of an individual on the principle of 11D10 administration can exhibit approximately 80% density (for example 80% of the cells exhibit HMFG). After receiving 11D10, a sample taken from the same site may exhibit only about 50% density, which indicates that HMFG-expressing cells are being destroyed. Similarly, if the intensity of spotting of a sample of an individual receiving 11D10 decreases upon receiving 11D10, this indicates that HMFG tumor cells in transit are being destroyed.
For the purpose of increasing an immune response, 11D10 can be administered in an unmodified form. It may sometimes be preferable to modify 11D10 to improve its immunogenicity. As used herein, "immunogenicity" refers to an ability to manifest a specific antibody or immune cellular response, or both. Methods of enhancing immunogenicity include, inter alia, cross-linking with agents such as gluteraldehydes or bifunctional couplers, or attachment to a polyvalent platform molecule. Immunogenicity can also be enhanced by coupling to a carrier protein, particularly one comprising T-cell epitopes.
The administration of 11D10 can take place alone or in conjunction with other forms of therapy, either established or experimental. "In conjunction with" means that 11D10 can be given concurrently with, before, or after other therapies. For example, 11D10 can be used as an adjunct to surgery, radiotherapy, chemotherapy and / or therapies of other medications, either concomitantly or seriously with respect to other therapies. The sequence and distribution of these administrations can be determined empirically and will depend on variables such as the disease being treated, the patient's condition, clinical history and indications, and / or response to various therapies. Such determinations are in the experience in the matter. The use of 11D10 in conjunction with the anti-idystype of the 3H1 antibody has been discussed above.
Preferably, 11D10 is administered before administration of another, adjunct therapies, such as chemotherapy and / or radiation, if these adjunct therapies have been used. Preferably, 11D10 is administered 1 day, preferably 3 to 5 days prior to each cycle of therapy by chemotherapy and / or radiation. This allows the individual more time to reach the immune response.
The administration of 11D10 may continue through several routes, depending on the individual being treated and the disease being treated. Preferably, the administration of 11D10 is continuous when an individual is able to reach an immune response, either humoral and / or cellular. The administration of 11D10 could be discontinuous if the individual presents unacceptable adverse reactions that are associated with the administration of 11D10, and can or can not be continued if the individual has progressive disease. The continuation of 11D10 administration in the case of progressive disease depends at least in part on whether the continuation of 11D10 administration could supplement other indicated therapies.
Determination of the Effects of the Administration of 11D10
In order to determine the effect of administration with 11D10, an individual can be monitored for either an antibody (humoral) or cellular immune response against HMFG, or a combination of these. The individual can also be monitored for progression of the disease.
To determine the level of antibody HMFG (Ab3) in a biological sample, for example, serum or plasma that are obtained from the individual. The sample can optionally be enriched with immunoglobulin before conducting the assay, however this is not usually required. If a mouse immunoglobulin (such as 11D10) is to be used as a test reagent, the sample is preferably prepared to remove the anti-mouse immunoglobulin activity. This can be effected, for example, by exhaustion on a column with mouse immunosglobulin, or by non-specific mixture of mouse immunoglobulin in the sample and removal of any immunoprecipitate formed.
To conduct the assay, anti-HMFG that may be in the sample is contacted with a non-limiting amount of an equivalent HMFG antigen. This can be isolated HMFG, nitrocellulose with HMFG added by direct spotting or by transfer on a polyaylamide gel, cells expressing HMFG (such as MCF-7 or SKBR-3 cells which are from the human breast carcinoma cell line ), preparation of the membranes of such cells, or sections of fixed tissues containing HMFG. alternatively, an anti-idiotype, particularly 11D10, can be used.
Once the immune complex has been formed, it is generally separated from uncomplexed analog HMFG, and the amount of complex present is determined. The complex can be separated, for example, by centrifugation to collect cells or an immunoprecipitate, or capture by a solid phase. The amount of complex present can be measured by providing the analog HMFG with a label either directly, or by incubation with a secondary reagent. Alternatively, a competition assay may be performed, in which the sample is first incubated with the analogous HMFG, and then a non-limiting amount of a labeled anti-HMFG reagent is added which competes with the anti-HMFg which may be present. in the sample. Suitable labels include radiolabels, enzyme labels, fluorescent labels, fluorescent and chemiluminescent labels. A standard curve is constructed using known solutions that do not contain anti-HMFG, and solutions with several relative concentrations of anti-HMFG, instead of the sample. The sample containing the unknown amount of anti-HMFg is generally tested in parallel, and a relative amount of anti-HMFG contained therein is determined by comparison with the standard curve. A preferred assay for determining levels of anti-HMFG using the HMFG antibody is the radioimmunoassay (Example 2).
The anti-HMFG antibody isotype can be determined by including in the immunoassay an isotype-specific reagent, either in the separation step or in the labeling. For example, anti-human IgG can be used to separate or detect antibody from the IgG class present in a clinical sample of human origin. The presence of anti-HMFG of the IgG class generally indicates a memory response. The presence of anti-HMFG of the IgM class generally indicates to continue the immunostimulation, in such a way that it may be due to the presence of a tumor expressing HMFG, continuing the HD10 treatment.
If desired, the anti-HMFG antibody detected in a biological sample can be further characterized; for example, by competition with anti-MC (Abl) to determine if they are specific for epitopes related to HMFG. Competing assays between Abl and Ab3 are described in Example 2.
The anti-HMFG antibody can be examined to determine if it is cytotoxic. The mediated complement cytotoxicity (CMC) is determined, for example, by use of target cells expressing HMFG (such as MCF-7 or SKBR-3) labeled with 51 Cr. Labeling can be achieved by incubating approximately 106 cells with ~ 200 μCi Na251Cr04 for 60 minutes at 37 ° C, followed by washing. The assay is conducted by incubating the antibody (or clinical sample containing the antibody) with the target cells. The ozonated cells are then washed and incubated with a complement source, for example, pre-adsorbed guinea pig serum to remove the intrinsic antibody activity. After a suitable incubation period at 37 ° C, the release of "Cr in the medium is determined and compared with that of the non-ozonized control cells.
The release of '-Cr correlates with activity
CMC.
Another way of characterizing the anti-HMFG antibody is by examining its ability to participate in an ADCC response (Cheresh et al. (1986 Cancer Res. 46: 5112-51118). Radiolabeled HMFGs expressing target cells are incubated with the anti-HMFG (in the form of thermally inactivated serum), and effector cells Normal human peripheral blood mononuclear cells (PBMC) are suitable effector cells, and preferably they can be used in an effector: target ratio of approximately 100. After approximately 4 hours at 37 ° C, the proportion of 51 Cr released is determined as a measure of ADCC activity.
The immune cellular response in a subject being administered 11D10 can be quantified by conducting standard functional assays for specific T cell activity.
One type of assay measures the proliferation of T cells. In this test, peripheral blood mononuclear cells (PBMC) are obtained from an integral sample of blood collected from the individual treated. For experimental animals, spleen cells can be used. T cells can be enriched, for example, by centrifugation on a gradient such as FICOL ™. The cells are then cultured in the presence of 11D10 or HMFG or (more usually) cells expressing HMFG irradiated at various concentrations. Preferably, the stimulator cells are analogous to the response cells, particularly in terms of the homologous compatibility of Class II antigens. The extent of proliferation is then measured (often in terms of ~ H-thymidine incorporation) compared to unstimulated cells. The proliferative activity of T cells in high-risk patients will be shown in Example 2.
Another type of assay measures the cytotoxicity of T cells. In this test, a population of enriched T cells is used for lysis effects of MMFG-51Cr-labeled target cell expression, prepared as described above. Preferably, the effector cells are autologous with the target cells, particularly in terms of histocompatibility of Ciase I antigens. The population of T cells can optionally be pre-stimulated with HMFG or a relevant cell line. The T cells are then combined in various proportions with approximately 104 target labeled cells; For example, in wells of a microtiter plate. The plate is optionally centrifuged to initiate cell contact, and the cells are cultured together for 4-16 hours at 37 ° C. The specific release rate of 51 Cr in the medium is measured in comparison with marked targets grown alone (negative control) and targets used with a detergent such as 0.1% TRITON ™ X-100 (positive control).
Other relevant measures to determine the effect of 11D10 administration include clinical tests that may be adequate to determine the development (for example progress) of cancer of a suspect type, either by direct or indirect indications of the piogress of the disease. Such tests may include blood tests, mammography, radioscintigraphy, CT scanning, and MRI. Any measurable variable that correlates with the progress of the disease is adequate. Any other tumor associated with a marker is suitable for monitoring the course of therapy, such as, for example, carcinoembryonic antigen (CEA), or CA-125.
The invention also includes the use of 11D10 for drug preparations for use in the treatment of HMFG-associated tumors, especially in individuals with low-weight tumors.
The following examples are provided to illustrate but do not limit the invention.
EXAMPLES
Example 1
Anti-idiotype production of 11D10 antibody by Immunization
The murine MC-10 murine antibody (which recognizes an epitope other than HMFG) was used to immunize BALB / c mice for the production of anti-idiotype antibody 11D1Q (IgGl-?) As described in our patent application no. 08 / 766,350 (authorized official number 30414/2000321). Immunization of BALB / c mice, hybridoma fusion and cloning, selection of anti-idiotype (Ab2) and production of ascites in bulk quantities in mice was given as previously described. Ab2 anti-idiotioi 11D10 (IgGl) was purified from ascites by affinity chromatography on protein A-CL Sepharose 4B column followed by ion exchange chromatography DEAE-Sepharose. The purity of the isolated immunoglobulin (> 95%) was determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and high pressure liquid chromatography techniques. Validation of tests for sterility, pyrogenicity, polynucleotides, mycoplasmas and contamination by adventitious viruses and removal of retroviruses. They were made in accordance with the United States Food and Drugs Administratisp manuals.
For use of 11D10 precipitated alumina, 1 ml alu -Gel S at 2% (Serva Fine Biochem, Inc., Carden City, Long Island, NY) was added to 5 mg aliquots of purified aanti-Id mAb (11D10). The volume is then adjusted to 10.0 ml with D-PBS and the mixture incubated on a vertex for one hour at room temperature. The mixture is then centrifuged at 200 rpm at 24 ° C for 10 minutes. The amount of mAb bound to the gel layer is determined by spectrophotometric measurement of the amount of unbound antibody in the supernatant. The antibody precipitated in the Alu Gel is stored at 4 ° C until its use. These procedures are performed aseptically in a laminar flow hood and the final product was sterile and clearly marked as anti-Id 11D10 Alu-Gel and aliquoted in sterile, pyrogen-free glass bottles.
For use with QS-21 or DETOX (TM) PC, 11D10 is embedded in only 2 mg / ml in sterile, pyrogen-free flasks.
Example 2
Use of 11D10 to treat High Risk Individuals in the Adjuvant Framework
Patient selection
High risk patients with positive HMFG tumors are selected for this study. These patients do not have advanced disease, for example, they do not have detectable metastasis. Generally, patients have received adjuvant chemotherapy and / or radiation therapy for breast cancer, lung cancer in non-small cells, or ovarian cancer. These patients usually received 11D10 on termination of treatment (typically at least four weeks after the end of treatment). Patients on hormone therapy received 11D10 concurrently with the treatment. So far, four patients have resulted in this study. Basic baseline studies include a complete physical examination, chest x-ray, abdomen examination by computerized axial tomography, and routine blood chemistry.
Preparation of Ab2
11D10 is obtained and precipitated to alumina or mixed with QS-21 or DETOX (TM) PC as described in example 1. The final product is examined for sterility, pyrogenicity and general safety in guinea pigs before use. A Request for Research on New Drugs was approved through the United States Food and Drugs Administration (BB-IND 5745). Before administration, 11D10 is thermally treated in the presence of adjuvant at 45 ° C for 30 minutes in a water bath. If the alumina is the adjuvant, 11D10 is heat treated in the presence of alumina. If QS-21 is the adjuvant, only 11D10 is heat treated.
Treatment Program All patients received 2 mg of 11D10 with adjuvant. Patients started one of three regimens: (a) 2 mg of 11 DIO - precipitated aluminum hydroxide (alumina); (b) 2 mg of 11D10 mixed with 100 μg of QS-21; (c) 2 mg of 11D10 mixed with DETOX ™ (250 μg CWS + 25 μg MPL®). For the regimen (c), 1.08 ml of 11D10 solution are mixed with 0.12 ml of DETOX ™ PC, and 1.0 ml is withdrawn for injection.
The injections are intracutaneous if the precipitated aluminum hydroxide is used. Injections are subcutaneous if QS-21 or DETOX ™ PC is used. Four injections are applied every two weeks, followed by monthly injections for a total of 24 months, while there is an unological response and no evidence of progressive disease. The patients were evaluated every twelve weeks. The patients were withdrawn from their study if they demonstrated progress of the disease.
Toxicity and Answers
Toxicity is monitored for each patient, including hematopoietic cell analysis, renal function, and liver function. Patients are also monitored very closely for disease activity.
Tests for Humoral Immunity
(a) Total anti-HDlO response
The development of humoral immunity induced by immunization with 11D10 is evaluated by examining the serum obtained from patients before therapy and after each treatment with the vaccine. The serum is initially examined for total antibody-anti-human murine responses including anti-iso / allo / and anti-anti-idiotype antibodies by radioimmunoassay sandwich as described by Khajaeli et al (1988) J. Nati. Cancer Inst. 80: 937-942. Briefly, microtitre plates are coated with 11D10 and incubated with different dilutions of patient sera. After washing, the antibody-antigen reaction was labeled using anti-Id 11D10 labeled in a homogeneous sandwich of radisinmunoassays. Since 11D10 is injected as intact IgGl, patients were expected to achieve human anti-mouse antibody responses.
(b) Specific response Ab3 to Ab2
Serum from patients immunized with positive HAMA responses is examined for the presence of anti-anti-idiotypic antibodies as follows. The serum is preincubated with normal urine immunoglobulin to block human antibodies against isotypes and allotypic determinants and then checked for the presence of anti-anti-Id (Ab3) by reaction with 11D10 coated on microtiter plates by RIA. Ab2 unrelated serve as a control. After washing, the antigen-antibody reaction is arcade using 11 1 -I-labeled in a homogeneous RIA sandwich as described above. The non-pretreated immune serum and serum from normal donors serve as controls.
If a positive reaction is obtained, the serum is checked for the ability to inhibit the binding of Abl (MC-10) 125I-labeled to Ab2 (11D10) on the plate by radioimmunoassay or vice versa (inhibition of radiolabelled Ab2 binding to Abl on the plate). These reactions occurred in the presence of excess murine normal immunoglobulin to block human antibodies against isotypic and allotypic determinants.
() Ab3 binding to tumor antigen
To evaluate the humoral immune response directed against native target antigens, serum Ab3 from patients is examined for reactivity with known cell lines to express the MC-10 antigen such as MCF-7 cells in an RIA and also by FACS analysis. MCF-7 cells are available from ATCC. In addition, the serum is checked to reactivity against a solubilized preparation is i-purified of antigen MC-10 (for example HMFG) and coated on microtiter plates. The antigen-antibody reaction is detected by using 125-human anti-Ig reagents, labeled. Pre-immune serum is used as a control. Unrelated antigen is also used in the assay. The isotype of Ab3 from human serum binding of MC-10 antigen is determined by ELISA using specific anti-human isotype reagents.
(d) Analysis of the Ab3 epitope
To demonstrate that Ab3 generated in treated patients and Abl (MC.10) bind to the same antigenic determinant, the inhibition of MC-10 binding to Ag-positive cell lines or the MC-10 antigen by serum Ab3 is checked by RIA . A fixed amount of radiolabelled MC-10 (~90,000 ccp) is co-incubated with different concentrations of purified preparations of Ab3 or Abl from patients and MCF-7 cells.
The Ab3 is purified from patient serum as follows. Fifteen milliliters of hyperimmune serum are passed over an immunoadsorbent column consisting of immunizing anti-idiotype immunoglobulin (11D10) coupled to Sepharose 4B. Anti-anti-idiotypic antibodies bound to the column are eluted with regulated glycine-0.1M hydrochloric acid (pH 2.4). the eluted antibody is neutralized with 3M Tris, dialyzed against PBS, pH 7.2 and then passed over an immunosorbent column consisting of allotype accompanied by normal mouse immunoglobulin coupled to Sepharose 4B to remove the anti-isotypic and anti-allotypic reactivities. The antibody that passes through is concentrated and used as purified Ab3. The isotype of Ab3 is determined by ELISA using specific anti-human isotype reagents (I 'ago).
The inhibition curves obtained with Abl and ab3 which are very similar at different dilutions indicate that the Ab3 of patients bind to the same antigenic epitope as abl and yet contain antibody molecules with Abl properties.
(e) Cytotoxic activities of Si ab3 in patient serum binds specifically to tumor cells, the ability of ab3 to lyse these cells together with effector cells and / or complement is examined by standard ADCC (Cheresh et al. (1986) or CMC assays). (Herlyn et al (1981) Int. J. Cancer 27: 769) However, the cytotoxic activity of Ab3 may depend on its isotype, IgG1 which is effective in ADCC and IgG1, IgG2, IgG3 and IgM in CMC.
Serum from patients is examined for ability to mediate antibody dependent cellular cytotoxic activity (ADCC). Cheresh et al. (1986). For this assay, cultures of human MCF-7 cells (expressing HMFG on the cell surface) are used as target cells and labeled with 51 Cr. Normal human peripheral blood mononuclear cells (PBMC) are used as effector cells. The ADCC assay is performed in the presence of heat-inactivated patient sera with an effector ratio to 100: 1 target cells for 4 hours, followed by measurement of the amount of 51 Cr released.
(f) Quantification of the response Ab3 and Abl
The expression of anti-anti-Id (Ab3) antibody in patient sera is quantified by RIA inhibition study co or follows. Briefly, microtiter plates are coated with MC-10 IgGl (Abl) and reacted with a fixed amount of I-labeled 11D10". A standard inhibition curve is generated using purified MC-10 IgGl as inhibitors. Next, patient serum depleted of anti-iso-allotypic activity at different dilutions is checked for its ability to inhibit the abl-Ab2 reaction and the amount of abl-probable antibody in the serum is estimated from the standard inhibition curve. The induction of the Ab3 response as well as the duration is compared between different adjuvants. If there are no statistical differences between Ab3 responses or duration at a number of doses, the titre of the specific anti-tumsr response (Ab1 ') in the serum per ELISA assay is compared against plates coated with semi-purified MC-10 antigen.
(f) In vitro studies
If the circulation of abl 'is not detected in the pool of positive Ab3 patients, which may indicate that they can be bound to tumor cells of the patients, or in the antigen of the tumor that circulates or they are of low affinity. These patient PBMCs are stimulated in vitro with antigen or Ab2 for the induction of the tumor specific antibody. For this, the PBMC obtained from blood collected before therapy, every three months, one month after the last immunization, and three months after the last immunization is cultured with various concentrations of 11D10, or unrelated Ab2, or MC- antigen. 10 (10 ug to 100 ng) in a cultivation of moodified Misheel-Dutton. Supernatant cultures are harvested and checked first for the production of specific human immunoglobulins by ELISA assay and for binding to the insolubilized preparation of ab2 by radioimmunoassay. In addition, the supernatants are examined for the content of idiotype carrier molecules for their ability to inhibit the reaction between labeled MC-10 (Abl) 125I and 11D10. Supernatants are also checked for their reactivity with MC-10 Ag-positive MCF-7 cells and Ag-negative cells such as M21 / P6 or MOLT-4 in a binding assay with reagents anti-human Ig 12oI-labeled by RIA or ELISA assay (sensitivity> 1 ng) for the evaluation of Abl 'antibody.
The specificity of the effect of 11D10 is monitored by incubation of PBMC with unrelated Ab2 of the same isotype. Since only positive Ab3 patients will be included in this study in vitrb, PBMC stimulated with 11D10 could secrete antibody that binds to 11 DIO and serve as a positive control.
Tests for mediated cell-mediated immunity.
The objective is to examine whether a specific T cell response to tumor-associated MC-10 antigen is generated in patients with tumor-associated HMFG, particularly breast cancer, following a series of immunizations with the anti-idiotype of 11D10 antibody in alumina or mixed with QS-21 or with DETOX ™ PC. Immunization with the vaccine could result in the generation of antibodies which alone can block the function of T cells. However, considering the importance of T cells in the anti-tumor response, particularly CTL, it is necessary to examine if this Immunological function exists.
T cell mediated immunity is checked by: 1) examining whether a T cell response whose target MC-10 antigens on tumor cells is present, and 2) examining whether the response increases with repeated immunizations. The procedure of analysis in two phases. The first phase is to determine if T cells of all received PBMC samples can be specifically expanded following in vitro immunizations against the anti-Id 11D10 antibody. if this occurs sdeter ina if these T cells can lyse or release cytokines against autologous MC-10 antigens carrying breast tumor cells and / or allogeneic MC-10 antigen expressing cancer cells that accompany a single HLA class I antigen in common with an autologous CTL.
All initiated patients who undergo felbotomy to collect a unit of whole blood prior to the first immunization. PBMC are isolated by standard Ficoll-Gypaque analysis and cryopreserved for all future studies. These PBMC provide 1) the antigen presenting feeder cells for subsequent studies, and 2) they serve as a baseline for T cell responses. In addition, following each immunization, 60 ml of peripheral blood is exudated, separated by Ficoll-Hypaque and cryopreserved for the determination of T cell responses.
The responses of T cells studied are the generation of cytotoxic specimens and / or cytokines that produce T cells and proliferation of T cell cultures in response to antigens. When biopsies of lymph nodes are available they are obtained from patients to provide a source of tumor that infiltrates lymphocytes (TIL). Similar studies are conducted when possible using TIL to determine if the tumor biopsy is converted into a source of cells specific for the MC-10 antigen. Khazaeli and colaboraodres (1998) J. Nati. Cancer Inst. 80: 937-942; Cheresh et al. (1985) Proc. Nati Acad. Sci. U.S. to. 82: 515. Also, tumor biopsies provide a source of tumor cells to serve as critical autologous targets for cytotoxicity assays, cytokine production, proliferation assays.
(a) Functional activity in vitr.o of T cells.
PBMC separated by Ficoll-Hypaque (1- 3 X 10 6) are incubated in the presence of: IL-2 alone (10 units Cetus / mi), 0.1 to 100 μg / ml of anti-Id 11D10 antibody or HMFG. The cell culture medium consists of Iscoves medium supplemented with 10% of human AB serum, gentamicin, sodium pyruvates, non-essential amino acids, L-glutamine and 10 units Cetus / ml of 11-2 recombinant. Every seven days the cultures are stimulated with irradiated autologous PBLs pre-synthesized with the appropriate antigen used on day 0. The in vitro sensitization methods are similar to those previously described (Steven et al. (1995) J. Immunol. 154: 762 ). Beginning on day 21 and repeated on a weekly basis, cell proliferation is evaluated for potential production of cytokines and cytotoxic and cell surface phenotype. Initially, all T cells are examined for their ability to recognize and use in 4 hours 51 Cr released from assays with autologous EBV cells alone and autologous EBV transfected into B cells with the cDNA containing the sequence for the anti-Id 11 DIO molecule. Cultures that lys transfected autologous EBV cells > 10% are additionally tested against the NK-sensitive K562 line, the Daudi LAK sensitive line, autologous tumors if available, and others accompanied by HLA and HMFG mismatched tumor cell carriers. In addition, GM-CSF is tested to determine if there is specific release of cytokines in addition to or in place of specific cyto-toxicity. The proliferation of the cultures in the agents is determined by an increase in the number of cells that continue in vitrs stimulations.
Survival results
Survival data are calculated based on the length of time in which a patient has no detectable disease (for example extension of time to progression). This extension of time is determined based on data entered in the study. A more statistically significant level is the extension of undetectable disease time (or for progress) as measured from the date of the last treatment.
Initial data of the study
The study described in this example was initiated. These data represent results since May, 1998, of a total of 14 patients enrolled in the study. Of the 14 patients, 11 were continuously receiving 11D10. Of the 3 patients who were excluded from the study, 2 were withdrawn after progressive disease (the other patient withdrew from the study). Six of the patients received QS-21; 3 of the patients received alumina (adjuvant data for the remaining patients are not available).
Of 10 patients examined for antibody response, all 10 showed Ab3 production. All seven patients examined for T cell proliferation showed an increase over baseline administration of 11D10 antibody, with several subsequent level patterns for this initial increase.
Six patients have been under study for more than 300 days, with two of the patients over the study over 400 days. For the two patients who showed progressive disease were 92 days for one patient and 119 days for the other patient (both of these patients were those who received QS-21). There were no deaths.
Example 3
Use of 11D10 to treat individuals with low-weight tumors
An individual who has been diagnosed as having a HMFG-associated tumor, such as breast cancer, is evaluated for the spread of the disease using standard imaging diagnostic techniques such as CT scanning. If the evaluation shows that the individual does not have advanced disease, preferably that it does not involve the lymph nodes, then the individual is given 11D10 in the same regimen as in Example 2. The individual is monitored for an immune response (see Example 2) and for extension of the disease. The treatment is continued while an immune response is maintained, even if the disease becomes undetectable by the methods described herein. The intervals between the administration of 11D10 may increase (for example longer than monthly) while an immune response is maintained and the disease does not appear to progress.
Example 4
Administration of 11D10 to an Individual at Risk of Developing HMFG-associated Tumor or who has Residual Disease
An individual who is considered to be at risk for developing a HMFG-associated tumor due to, for example, family history of HMFG-associated tumors, is administered 11D10 biweekly (or as often as twice a week) until a immune response
(see Example 2). From the manifestations of an immune response, the interval between administrations of 11D10 is increased to once a week for each administration until the immune response begins to decrease. The interval between administrations of 11D10 is then sequentially adjusted to the previous intervals until the immune response remains constant (for example it does not decrease further). The administration of 11D10 is maintained in that interval. The individual is monitored for the development of the disease every one or two years.
As a more particular example of this procedure, a 33-year-old woman chosen to start the 11D10 administration based on her family history of breast cancer HMFG = associated (mother, grandmother, and aunt had developed the disease). Injections started on a biweekly basis until an immune response is detected (usually 1 to 4 months). The next injection is given after a week. The following injections are given as follows: (a) after two weeks, then, (b) after three weeks, then (c) after four weeks, then (d) after five weeks, then, (e) after of six weeks, then, (f) after seven weeks, then (g) after 8 weeks. The injections are maintained every two months while the immune response is monitored every month. If the immune response is constant, the injections are given as follows: (a) every 9 weeks, then (b) every 10 weeks, then
(c) every 11 weeks, then (d) every 12 weeks. The injections are maintained every three months while the immune response is monitored. If the immune response is constant, the intervals between the injections of 11D10 are increased by one week until the injections are given every 6 months. If the immune response declines, then the interval is shortened until the immune response is restored to its original level. The individual is kept on adiminstarcisnes of 11D10 during his life time. If HMFG-associated tumors develop, then other therapies can be administered in conjunct or instead of, 11D10.
As another particular example, an individual with HMFG-associated breast cancer had the tumor resected, and there is no knowledge of involvement of lymph nodes. The disease is not detectable after surgery. The administration of 11D10 begins and is adjusted as described above, and the individual is monitored for disease progression.
Example5
Administration of 11D10 in the Neo-Adjuvant setting
An individual who has been diagnosed with a HMFG-associated tumor, such as an HMFG-associated breast or ovarian cancer, is scheduled to obtain treatment such as chemotherapy surgery. During the time between diagnosis and the start of treatment (for example, while the patient is waiting for this treatment to begin) 11D10 is administered as described in example 2. The administration of 11D10 continues after the start of this treatment and during the course of this treatment. The interval between the administration of 11D10 is adjusted so that the individual maintains an immune response.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will appear to those skilled in the art that certain changes and modifications may be practiced. Accordingly, the description and examples may not be construed as limiting the scope of the invention, which is delineated by the appended claims.
LIST OF SEQUENCES
;1. GENERAL INFORMATION:
: i) APPLICANT: Chatterjee, Malaya Foon, Kenneth A.
(ii) TITLE OF THE INVENTION: METHODS FOR DELAYING THE DEVELOPMENT OF HMFG-ASSOCIATED TUMORS USING ANTI-IDIOTIDE OF ANTIBODY 11D10
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(vi) DATA OF THE APPLICATION:
(A) APPLICATION NUMBER: USA (B) REGISTRATION DATE (C) CLASSIFICATION:
(viii) - INFORMATION OF THE OFFICER / APPORTER;
(A) NAME: Pzi, catherine M. (B) REGISTRATION NUMBER: 40,130 (C) REFERENCE / NO ACTION: 30414-20006.00
(ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: (650) 813-5600 (B) TELEFAX: (650) 494-0792 (C) TELEX: 706141
(2) INFORMATION FOR SEQ ID NO: 1
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(ix) CARACETRISTIICAS:
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(xi) DESCRIPTION OF SEQUENCE SEQ ID NO. 1;
ATG GGG GCC CCT GCT CAG ATT CTT GGG TTC TTG TTG CTC TTG TTT CCA 48 Me- Gly Ala Pro Wing Gln lie Leu Gly Phe Leu Leu Leu Leu Phe Pro -20 -15 -10 -5 GGT ACC AGA TGT GAC ATC CAG ATG ACC CAG TCT CCA TCC TCC TTA TCT 96 Gly Thr Arg Cys Asp lie Gln Met Thr Gln Ser Pro Ser Ser Leu Ser 1 5 10 - GCC TCT GG CAG AGA CAG AGTC CTC ACT TGG CGG CAG GAC CAG GAC AGG 14-1 Wing Leu Gly Gin Arg Val Ser Leu Thr ys Arg Ala er Gln Asp 15 20 25 ATT GGT ATT AAC TTA CAT TGG CTT CAG CAG GAA CCA GAT GGA ACT Am'm 1S2 He Gly lie Asn Leu His Trp Leu Gln Gln Glu Pro Asp Gly Thr lie 30 35 40 AAA CGC CTG ATC TAC GCC ACÁ TCC AGT TTA GGT TCT GGT GTC CCC AAA 240
Ly = Arg Leu lie Tyr Ala Thr Ser Ser Leu Gly Ser Gly Val Pro Lys 45 50 55 60 AGG TTC AGT GGC AGT AGG TCT GGG TCA GAT TAT TCT CTC ACC ATC AGC 288 Arg Phe Ser Gly Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr lie Ser 65 70 75 AGC CTT GAG TCT GAA GAT TTT GTA GCC TAT TAC? GT CTA CAA TAT GCT 336 Ser Leu Glu Ser Glu Asp Phe Val Ala Tyr Tyr Cys Leu Gln Tyr Ala SO 85 90 AGT TCT CCG TAC ACG TTC GGA GGG GGG ACC AAG CTG GAA ATA AAA CGG 38. Be Ser Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu lie Lys Arg 95 100 105 GCT GAT GCT GCA CCA ACT GTA TCC ATC TTC CCA CCA TCC AGT AAG CTT 432 Wing Asp Ala Ala Pro Thr Val Ser lie Phe Pro Pro Ser Ser Lys Leu 110 115 120 GGG 435 Gly 125
INFORMATION FOR SECTION ID NO:
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Met Gly Ala Pro Ala Glr. I read: Gly Phe Leu Lau Leu Leu Phe Pro -20 -15 -10"-5
Glv Thr Arg Cys Asp He Glr. Met Thr Gln Ser Pro Ser Ser Leu Ser 1 5 10 Wing Being Leu Gly Gin Arg Val Being Leu Thr Cys Arg Wing Being Gln Asp 15 20 25 He Giv He Asn Leu His Trp Leu Gln Gln Glu Pro se GJ and Thr He
35 40 Lys Arg Leu He Tyr Ala Thr Ser Ser Leu Gly Ser Gly Val Pro Ly =
45 50 55 6C
Arg Phe Ser Gly Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr He Ser 65 70 75
Being Leu Glu Being Glu Asp Phe Val Wing Tyr Tyr Cys Leu G n Tyr Ala
80 85 90 Ser. Ser Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu GI. He ys Arg
95 100 105 Wing Aso Wing Wing Pro Thr Val Ser He Phe Pro Pro Ser Ser Lys Leu
110 H5 120 Gly 125
[2) INFORMATION FOR SEQ ID NO: 3: (i) CHARACTERISTICS OF THE SEQUENCE:
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(ii) TYPE OF MOLECULE: DNA (GENOMIC) (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1 ... 459
(ix) CARACETRISTIICAS:
(A) NAME / KEY: mat_PEPTIDE (B) LOCATION: 58
(xi) DESCRIPTION OF SEQUENCE SEQ ID NO.
ATG GAA TGC AGC TGG GTC TTT CTC TTC CTC CTG TCA ATA ACT ACÁ GGT .8
Met Glu Cys - Ser Trp Val Phe Leu Phe Leu Leu Ser He Thr Thr Gly -19 -15 -10 -5 GTC CAC TCC CAG GCT TAT CTA CAG CAG TCT GGG GCT GAG CTG GTG AGG 96
Val His Ser Gln Wing Tyr Leu Gln Gln Ser Gly Wing Glu Leu Val Arg 1 5 10 TCT GGG GCC TCA GTG AAG ATG TCC TGC AAG GCT TCT GGC TAC ACA TTG 1 1. Ser Gly Wing Ser Val Lys Met Ser Cys Lys Wing Ser Gly Tyr Thr Leu 15 20 25 ACC AGT TAC AAT ATG CAC TGG GTA AAG CAG ACÁ CCT GGA CAG GGC CTG 192 Thr 3rd Tyr Asn Me- His Trp Val Lys Gln Thr Pro Gly Glp Gly Leu 30 '35 40 45 GAA TGG ATT GGA AAT ATT TTT CCT GGA AAT GGT G? T ACT TAC TAC AAT 24C Glu Trp He Gly Asn He Phe Pro Gly Asn Gly Asp Thr Tyr Tyr Asn 50 55 SO CAG AAG TTT AAG GGC AAG GCC TCA TTG ACT GCA GAC ACÁ TCC TCC AGC 288
Gln Lys Phe Lys Gly Ly = Wing Ser Leu Thr Wing Asp Thr Ser Ser Ser 65 70 75 ACÁ GCC TAC ATG CAG ATC AGC AGC CTG ACÁ TCT GAA GAC TCT GCG GTC. 336 Thr Ala Tyr Met Gln He Ser Ser Leu Thr Ser Glu Asp Ser Wing Val TAT TTC TGT GCA AGA GGG AAC TGG GAG GGT GCT CTG GAC TAC TGG GGT 384 Tyr Phe Cys Wing Arg Gly A = n Trp Glu Gly Wing Leu Asp Tyr Trp Gly 95 100 105 CAA GGA ACC TCA GTC ACC GTC TCC TCA GCC AAA ACG ACA CCC CCC CCA 432 Gln Gly Thr Ssx Val Thr Val Ser Ser Aja Lys Thr Thr Pro Pro Pro 110 115 120 125 GTC TAT CCA CTG GTC CCT GGA AGC TTG GG 451
Val Tyr Pro Leu Val Pro Gly Ser Lau 130
(2) INFORMATION FOR SEQ ID NO: 4 (i) CHARACTERISTICS OF THE SEQUENCE:
(A) LENGTH: 153 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear
(ii) TYPE OF MOLECULE: PROTEIN
(ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1 ... 435
(ix) CARACETRISTIICAS:
(A) NAME / KEY: mat__PÉPTIDO (B) LOCATION: 61 (xi) DESCRIPTION OF SEQUENCE SEC ID NO. 4: Met Glu Cys Ser Trp Val Phe Leu Phe Leu Leu Ser He Thr Thr Gly -19 -15 -10 -5 Val His Ser Gln Wing Tyr Leu Gln Gln Ser Gly Wing Glu Leu Val Arg 1 5 10 Ser Gly Wing Ser Val Lys Met Ser Cys Lys Wing Ser Gly Tyr Thr Leu 15 20 25 Thr Ser Tyr Asn Met His Trp Val Lys Gln Thr Pro Gly Gln Gly Leu 30 35 40 45 Glu Trp He Gly Asn He Phe Pro Gly Asn Gly Asp Thr Tyr Tyr Asn 50 55 60 Gln Lys Phe Lys Gly Lys Wing Ser Lsu Thr Wing Asp Thr Ser Ser Ser 65 70 75 Thr Wing Tyr Met Gln He Ser Ser Leu Thr Ser Glu Asp Ser Wing Val 80 - 65 90 Tyr Phe Cys Wing Arg Gly Asn Trp Glu Gly Wing Leu Ase Tvr Tro Gly 95 100 105 Gln Gly Thr Ser Val Thr Val Ser Ser Wing Lys Thr Thr Pro Pro Pro 110 115 L? A 125 Val Tyr Pro Leu Val Pro Giy Ser Leu 130
It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.
Having described the invention as above, it is claimed as property in the following:
Claims (22)
1. A method of retarding the development of a HMFG = associated tumor in an individual having a low weight tumor, which is characterized in that it comprises administering an effective amount of 11D10 antibody anti-idiotype to the individual.
2. The method of claim 1 which is characterized in that the individual is at high risk.
3. The method of claim 2, which is characterized in that the individual is in the adjuvant frame.
4. The method of claim 1, which is characterized in that 11D10 is administered with an adjuvant.
5. The method of claim 4, which is characterized in that the adjuvant is aluminum hydroxide.
6. The method of claim 1, characterized in that the HMFG-associated tumor is in the breast.
7. The method of claim 1, which is characterized in that 11D10 is administered in an amount of about 1 mg to about 4 mg.
8. The method of claim 1, which is characterized in that 11D10 is administered in an amount of about 2 mg.
9. The method of claim 1, which is characterized in that 11D10 is administered at weekly intervals.
10. The method of claim 1, which is characterized in that 117D10 is administered at biweekly intervals.
11. The method of claim 1, which is characterized in that 11D10 is heat treated prior to administration.
12. A method of treating a HMFG-associated tumor in an individual with a low-weight tumor that is characterized in that it comprises administering an effective amount of anti-idiotype of the 11D10 antibody to the individual.
13. The method of claim 12, which is characterized in that the individual is at high risk.
14. The method of claim 13, which is characterized in that the individual is in the adjuvant frame.
15. The method of re-irradiation 12, which is characterized in that 11D10 is administered with an adjuvant.
16. The method of claim 15, which is characterized in that the adjuvant is aluminum hydroxide.
17. The method of claim 12, which is characterized in that the HMFG-associated tumor is in the breast.
18. The method of claim 12, which is characterized in that 11D10 is administered in an amount of about 1 mg to 4 mg.
19. The method of claim 12, which is characterized in that 11D10 is administered in an amount of about 2 mg.
20, The method of claim 12, which is characterized in that 11D10 is administered at weekly intervals.
21. The method of claim 12, which is characterized in that 11D10 s administered at bi-weekly intervals.
22. The method of claim 12, which is characterized in that 11D10 is heat treated prior to its administration.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US049540 | 1997-06-13 | ||
US60/049540 | 1997-06-13 | ||
US096244 | 1998-06-11 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA99011526A true MXPA99011526A (en) | 2000-06-01 |
Family
ID=
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