Patent for “Methods to treat recurrent hematological malignancies.”

Therapeutic Antibodies – Pascale Andre, Renaud Buffet, Marcel Rozencweig, Jerome Tiollier, Innate Pharma SAS

Search Patent for “Methods to treat recurrent hematological malignancies.”

Abstract for “Methods to treat recurrent hematological malignancies.”

“Compositions containing compounds that neutralize NK cells inhibitory receptors are described. Also, methods for using such compositions to treat hematological malignancies.”

Background for “Methods to treat recurrent hematological malignancies.”

Natural killer (NK) cells is a subset large granular lymphocytes which act as cytotoxic immune cell. The cytotoxic activity mediated naturally by NK cells against target cells (e.g. cancer cells, viruses infected cells) can be described as a result of a?balance’. “A combination of positive and negative signals transmitted by activated and inhibitory cell surface receptors.”

“NK cells are identified using any of the known cell surface markers. These markers vary from species to species. In humans, CD56, CD16 and NKp44 are used. In mice, Ly49A, CD49b, and CD49b are used. NK cells can kill certain types of autologous, allogeneic and even xenogeneic tumors, virus-infected cell lines, and certain bacteria in an active state. NK cells seem to preferentially kill target cell types that express low or no Major Histocompatibility Classes I (?MHCI?) ?MHCI? molecules on their surfaces. NK cells can also kill target cells that have antibody molecules attached. This is known as antibody-dependent cellular cytotoxicity. NK cells may release pore-forming proteins known as perforins and proteolytic enzymes called granzymes. They also can release cytokines/chemokines such as TNF?, IFN??, etc. These can directly cause apoptosis of target cells or regulate immune responses. NK cells may also express Fas ligand, which allows them to induce apoptosis of Fas-expressing cells upon activation.

“Sufficient NK cells activity and NK count are usually required to mount an adequate NK-mediated immune response. Although NK cells are present in normal amounts in an individual’s body, they will not be activated to perform vital immune system functions such as the elimination of abnormal cells. A decrease in NK cell activity can lead to many diseases. Research has shown that low NK cells activity is linked to the development and progression of many diseases, including chronic fatigue syndrome (CFS), viral infection, and cancer.

“NK cell activity modulating receptors (?NKCAMRs) regulate NK cell activity. Or simply?AMRs. ), which can be specific for ligands like MHC-1 molecules, MHC-1 homologs, and other biological molecules expressed on target cell cells. A number of activating receptors and inhibitory receptors are common in NK cells. These activating and inhibitory receptors regulate NK cell activity. Below is a brief overview of each type of NKCAMR. The majority of NKCAMRs belong to one of two types of proteins: the immunoglobulin Ig)-like superfamily (IgSF), or the C-type lectin?like receptor (CTLR superfamily) (see Radaev, Sun, Annu). Rev. Biomol. Struct. 2003 32:93-114). Other forms of NKCAMRs, however, are also known.

Antibodies against NKCAMR have been described previously. There has also been some suggestion that anti-NK receptor antibodies (such as anti-KIR antibodies) could be combined with other anticancer agents. WO2004056392, for example, describes anti-NKp30/or anti-NKp46 antibodies that are used in admixture of interleukin-2. WO2005009465 describes combining a therapeutic antibody (e.g. Rituxan) with a compound that blocks a inhibitory receptor or stimulates a activating receptor of a NK cell (e.g. an anti-KIR mAb such as the mAb DF200 or anti-NKp30 mAb). This combination is intended to increase the effectiveness of treatment with therapeutic antibodies in humans (see also US 20050037002). WO2008/084106 outlines anti-KIR dosages, formulations, and dosing regimens. WO2005079766 describes combinations of antibodies, such as anti-tissue factor antibodies. This includes anti-KIR antibodies that can be used in cancer treatments. WO2005003168, WO2005003172 and WO2005003172 both describe anti-KIR antibody combinations with a variety agents including IL-2 or IL-21. WO2005037306 also describes anti-KIR antibodies in combination with IL-21, IL-21 derivatives and IL-21 analogs.

“NK cells have attracted a lot of attention for their potential contribution in anti-tumor immune responses mediated through antibodies that bind to tumor antigens. However, very few studies have focused on the in vivo efficacy and potentiation of NK cell cytotoxicity by modulating NK receptors. NK cell modulating substances have been shown to potentially restore NK cells’ ability to kill target cells. These treatments are not recommended for patients with advanced disease. This may be because there is evidence that NK cells immunosurveillance is affected by significant disease (e.g. tumor burden). In myeloma, for example, there is an association between aggressive multiple myeloma and functional exhaustion. Patients with advanced MM also experience a decline in NK cell counts and hyporesponsiveness to stimulation.

“There is a need for improved methods to use NK cell modulation to benefit patients. Particularly useful for the treatment of cancer are compounds that modulate NK cells activity, such as anti-+NKCIR antibody fragments and other similar compounds.

“The invention provides methods to treat an individual who has or had a pre-malignancy or hematological malignancy. These methods involve administering to an individual a therapeutically active dose of a compound that inhibits a NKCIR (NKCell Inhibitory Receptor). Preferably, the compound is administered to the patient at a time when there is minimal or no detectable disease. The invention also contemplates the use of a compound inhibiting a NKCIR, which is a compound that can be used to treat a person with hematological premalignancy or hematological cancer. This composition will contain a therapeutically active dose of a compound that inhibits a natural killer cell inhibitor receptor.

“One embodiment of the invention indicates that the individual has hematological premalignancy. A particular embodiment of the invention describes an individual with SMM (smoldering meloma), MGUS [monoclonal gammopathy undetermined significance] or MDS (myelodysplastic disorder).

“In another embodiment, the individual has or has previously had a hematological cancer or a genetic mutation that increases the likelihood of developing a hematological tumor. A particular embodiment states that the individual has previously had lymphoma or lymphoma or other lymphoid malignancies. Preferably, the individual has/had AML (acute meloid leukemia), MM(multiple myeloma), SMM [smoldering myeloma], CML (chronic minelogenous leukemia), CLL (chronic lymphocytic lung disease), or SMM (smoldering meloma).

“In one embodiment, the patient has received a first treatment for hematological malignancy/hematological premalignancy before administering the compound. You can choose from a chemotherapeutic, immunomodulatory, radiotherapy, surgery, anti-hormone, anti-angiogenic, or combination of these treatments. The individual should have experienced either a partial or complete response to the initial treatment. The first treatment may have resulted in the individual being in remission, a non-detectable condition, asymptomatic and/or having a low number of abnormal cell counts.

“An embodiment of hematological malignancy, which is AML, is a leukemia. The individual should be in remission, have no symptoms, not have a detectable disease and/or have a small number of abnormal cells. This can happen after treatment with the first. A particular embodiment shows that the patient has a total body leukaemia burden of less than 109 cells,/or less 5% blasts within the marrow, and/or is free from signs and symptoms associated with leukemia.

“In one embodiment, the hematological cancer is a myeloma. This is multiple myeloma (MM). The individual should have experienced a partial or full response and be symptomatic. A particular embodiment shows that the patient has seen a more than 25% decrease in serum protein M levels. The individual should have experienced a serum protein level reduction of at least 50%.

“In one embodiment, the hematological cancer is smoldering multimyeloma (SMM). The individual should have experienced a partial or full response and be asymptomatic. A particular aspect of the invention states that the individual must have 10% or more bone marrow plasma cells, but not enough to meet the criteria for multiple myeloma. Another aspect of the invention states that the individual’s serum M protein level is 3 g/dL. Another aspect of the invention states that the individual has at least 10% of its bone marrow plasma cells and no evidence of end organ damage (CRAB). A further embodiment shows that the individual has serum M protein of?3 g/dL, and has 10 percent or more plasma cells within the bone marrow. This optionally leaves no evidence for end-organ damage.

“In one embodiment, the hematological cancer is monoclonal gammopathy with unknown significance (MGUS). The individual should have less than 10% of the bone marrow’s plasma cells in such an embodiment.

“The invention also includes methods that include:

“(a) To determine if an individual with a hematological cancer has minimal or not-detectable disease;

“(b), if the individual is not suffering from any disease, administer a therapeutically active dose of a compound that inhibits the NKCIR to the individual.”

“Moreover, the invention also includes methods consisting of:

“(a) determining if an individual has a smoldering multimyeloma, an asymptomatic monoclonal gammopathy or a myelodysplastic disorder (MDS).”

“(b), if an individual has SMM or MGUS, treating them with a therapeutically effective amount of a compound which inhibits a NKCIR.

“Furthermore the invention also includes methods that include:

“(a) Treating an individual with a hematological cancer using a first treatment (e.g. one or more induction treatments and optionally one/more consolidation therapies), optionally wherein one or more chemotherapeutic agents or immunomodulatory agents, e.g. an Imid, is used. The individual is found to have minimal or no detectable disease (e.g. the disease is in remission or the individual experiences a response after the first treatment).”

“(b) Treating the individual with minimal or non-detectable illness using a therapeutically active dose of a compound that inhibits NKCIR. Optionally, step (a), may also include determining if an individual with a hematological cancer has minimal or not-detectable disease.

“Additionally, this invention contemplates using a compound to prepare a composition that detects if an individual has had or has had a hematological cancer. If the individual has minimally or non-detectable diseases, treatment with a therapeutically effective amount of a compound that inhibits NKCIR can be done.”

“The invention also contemplates using a compound to prepare a composition that detects whether an individual is suffering from a smoldering myeloma, an asymptomatic monoclonal-gammopathy (MGUS), or a myelodysplastic disorder (MDS). If the individual SMM, MGS, or MGUS, the treatment will be with a therapeutically effective amount of a compound that inhibits NKCIR.”

“In addition, the invention allows for the use of a compound to prepare a composition that can be used to treat an individual suffering from a hematological cancer. The first treatment is designed to treat the individual with minimal or no detectable disease. Treatments are then given using a therapeutically active compound that inhibits the NKCIR.

“In one embodiment, determining if an individual with or having had a hematological cancer has minimal or not-detectable disease, has a partial response or complete response and/or has a specific pathology (e.g. SMM, MGUS. AML. CML. MDS. MM. Standard medical guidelines are used to determine whether the individual has a hematological malignancy.

“In one embodiment, the identification of abnormal cells or abnormal numbers of cell populations (e.g. percentage of plasma cells found in bone marrow) is used to determine if an individual with or having had a hemorhagic malignancy is in remission. Optionally, this identification can be done by flow cytometry. Optionally, the method can also be used to sort or isolate abnormal cells.

“One embodiment of determining whether a person with or having had a hemorhagic malignancy is in remission or has a complete response involves detecting cytogenetic aberrations, such as assessing the karyotype.

“In one embodiment, the detection of minimal illness involves sorting the abnormal cells and contacting the nucleic acid with one or more nucleic agents that target a genetic rearrangement that correlates with increased likelihood of the onset a hematological Malignancy. The contacting determines the existence of cytogenetic aberrations, thus detecting minimal disease. One embodiment of the genetic marker is a mutation or deletion in FLT3 and NpM1 which correlates with poor survival prospects for individuals with AML. Another embodiment is a rearrangement of the Immunoglobulin Ig and/or T Cell receptor genes.

“In one embodiment, the assessment of serum monoclonal proteins (M) is used to determine if an individual with or has had a hematological cancer has minimal or not-detectable symptoms.

“In one embodiment, the determination of whether an individual has SMM/MGUS involves assessing the serum monoclonal proteins (M protein) levels in the individual. Optionally, the patient may be determined to have SMM if M protein levels are at least 3g/dL. One embodiment of determining whether someone has SMM/MGUS involves assessing bone-marrow plasma cell levels in the individual.

“As we have discussed, a patient with a poor prognosis (e.g. is at higher risk of progression) is based on one or more predictive variables. According to Table 2, the patient with SMM is in Group 1. One embodiment shows a patient with poor prognosis due to gene mutations. For example, the patient may have AML and a mutation in FLT3/NpM1 that is associated with poor prognosis.

“In one embodiment, the compound inhibiting a NKCIR can be used as a single agent. Another embodiment uses the compound that inhibits NKCIR in combination with at most one other therapeutic agent.

“The compound that inhibits a NKCIR could modulate NK cells cytoxicity because it inhibits said NKCIR. The preferred compound that inhibits a NKCIR should be an anti-NKCIR antibody or fragment with the ability to block NKCIR-mediated NK inhibition, and thereby increase NK cell activity towards other blocked cells. The antibody or fragment of an antibody is, in one embodiment, an antibody against a killer immuneglobulin-like (KIR), or a fragment thereof. Another embodiment of the antibody or fragment is a humanized, chimeric or humanized antibody. Another embodiment of the antibody or fragment is an IgG1, IgG2, IgG3, IgG4, IgD or IgE. The preferred antibody or fragment of an antibody comprises an IgG1 and IgG4. One embodiment of the antibody or fragment includes a Fc domain that contains at least one mutation that affects one effector function, half life, proteolysis or glycosylation.

“In a specific embodiment, the anti-KIR antibody/antibody fragment is an anti?KIR antibody or antibody fraction that binds KIR2DL1 or KIR2DL2/3. The anti-KIR antibody/antibody fragment should compete with 1-7F9. Preferably, the anti-KIR fragment or antibody antibody is 1-7F9, or a part thereof. The anti-KIR antibody fragment could also be a 1-7F9 fragment that exhibits the same binding properties and functions as 1-7F9. One aspect of the anti-KIR antibody/antibody fragment is that it contains VL and VH domains that are at least 90% identical with those of 1-7F9. Another aspect is that the anti-KIR antibody/antifragment comprises the VL domains and VH domains from 1-7F9. Another aspect is that the anti-KIR antibody/antibody fragment’s VL includes the 1-7F9 VL CDRs. A further aspect is that the VH of anti-KIR antibody/antibody fragment includes the VH CDRs from 1-7F9.

“In one embodiment, anti-KIR antibody/antibody fragment consists of a polypeptide whose sequence is at least 80% to 1-7F9 or at most 90% to 1-7F9 or at least 95% to 1-7F9 or at least 98% to 1-7F9. Another embodiment of the anti-KIR antibody/antibody fragment binds to the exact same linear/conformational epitope on an unchanged KIR2DL1/KIR2DL2/3 as 1-7F9 and/or competes for binding to that linear/conformational epitope upon an intact KIR2DL1/KIR2DL2/3.

“Another embodiment of the antibody of antibody fragment is an anti-NKCIR antibody selected from the group consisting CD94, NKG2E and NKG2A, and LIR (e.g. LILRB1 through B5) or a fragment thereof.”

“In one embodiment, the antiNKCIR antibody can be administered as a pharmaceutically acceptable mixture containing a therapeutically-effective amount of the antiNKCIR antibodies. One aspect of the invention is that the NKCIR antibody should be administered in a way that results in a substantial saturation of the NKCIR by NK cells for a minimum of one week, at most about two weeks or for preferably one month.

“In one aspect, the antibody dosed at a frequency and in an amount that substantially completes saturation of NKCIR on NK cell for a time of at least 1 week or about 1 month with no significant?de-saturation? During the treatment period. One embodiment of therapeutically active NKCIR antibodies is a dose that causes NKCIR saturation to be substantially complete on NK cells within a time period of at least 1 week, 2 weeks, or 1 month. The antibody is administered multiple times at a frequency of about once every 2 weeks, once every 3 months, or once every 4 months. After the first dose, the next dose is separated by approximately 2 weeks or about one month.

“In one aspect, the antibody dose and frequency is such that the NKCIR on NK cell cells is substantially saturated for at least 1 week or 2 weeks. This allows significant?de saturation? During the treatment period. One embodiment of therapeutically active NKCIR antibodies is a dose that causes NKCIR saturation to be substantially complete on NK cells for at least one week, two weeks, or one month after administration. The antibody is administered multiple times at a frequency of one every two weeks, one every three months, or one every two months. Subsequent doses are separated by approximately 2 weeks or one month.

“In another embodiment, anti-NKCIR antibody/antifragment is administered in a range of about 0.01 mg/kg up to 3.0 mg/kg. It can also be administered at a dose of about 0.1 mg/kg up to 1.0 mg/kg. Or, a dose range of 1.0 mg/kg up to 3.0 mg/kg. The anti-NKCIR antibody and/or antibody fragment should be administered approximately once every two months.

“Another aspect is that any of the above-described treatments may optionally be modified with the addition of one or more anti-cancer drugs, e.g. chemotherapy agents.

“Another embodiment provides pharmaceutical compositions for human treatment that contain an antiNKCIR antibody, fragment, or antibody according to the invention, and a pharmaceutically acceptable carrier, or excipient. These pharmaceutical compositions, upon administration to an average subject (about 45-90kg in weight), result in a dosage range ranging from about 0.01 mg/kg up to about 3.0mg/kg, approximately 0.3mg/kg up to about 3.0mg/kg, approximately 0.1 mg/kg up to about 1.0m/kg or about 1.0m/kg or about 1. Specific embodiments of composition on administration to an average human subject result in a dosage range between 0.1 and0.3 mg/kg and more precisely 0.2 mg/kg and about 0.3 mg/kg.

The invention also includes methods of treating a person with a disease or for enhancing NK cell activity in someone who is in need. The procedure involves administering an anti-NKCIR or fragmented antibody to an individual in an amount of about 0.01 mg/kg to about 0.3% mg/kg in a human subject. A pharmaceutically acceptable carrier is used. The anti-NKCIR or fragment is not to be administered more than once per month. The invention also allows for the administration of anti-NKCIR antibodies or fragments in amounts that range from about 0.1 mg/kg up to about 0.3 mg/kg for humans. A pharmaceutically acceptable carrier is used for the preparation of human therapy. One embodiment of the invention states that the anti-NKCIR antibody and/or antibody fragment should be administered only once every two months. Another embodiment administers the anti-NKCIR antibody/antibody fragment between once per month, and once every two weeks. Another embodiment provides the anti-NKCIR antibody/antibody in a dose of approximately 0.1 mg/kg to 0.2 mg/kg in a patient.

These aspects are described more in detail in the description of this invention. Additional features and advantages of the invention will also be evident from it.

Summary for “Methods to treat recurrent hematological malignancies.”