TWI280137B - Treatment of intermediate-and high-grade non-Hodgkins lymphoma with anti-CD20 antibody - Google Patents

Abstract

This invention discloses methods for the treatmentof intermediate- and high-grade non-Hodgkins lymphomas comprising administration of anti-CD20 antibodies.

Description

V. DESCRIPTION OF THE INVENTION (1) Invention φ The present invention is a highly non-Hodge method. The invented non-Hodgkin American Cancer Society 6 5 % of the patients classified as j patients in the diagnosis of moderate or high disease in patients with common tumors, often used to treat appropriate donors may There are all kinds of patients who are treated in the treatment, the body. This antibody died. Or the human anti-CD20 monoclonal antibody and its fragment for the treatment of Jin's lymphoma, and the high-quality bone marrow containing 'X and heart lymphoma, the characteristic of the c-slip is the malignant growth of B lymphocytes. . It is estimated that there will be 5 4, 〇 〇 new medical records will be diagnosed, with moderate or high lymphoma. He was diagnosed with also, and the middle of the sheep was 2 to 5 years, and he was diagnosed with high-grade P-disability and survived for an average of 6 months to 2 years. J: 2 is more white in the diagnosis of mild lymphoma. The oral therapy can survive on average for 5-7 years. Moderate or ::ί: extranodal giant tumors and multiple circulatory cancers in the bone marrow of patients. ^ ;, 3 including chemotherapy and radiation therapy, if available, if the bone harvesting day contains too many tumor cells, then the same or the same kind of bone marrow or stem cell transplantation. Patients often have a habit of using it = but it usually recurs within a few months. = Xin Lai 1 treatment of non-Hodgkin's lymphoma has been used in the treatment of the use of finger bow to the surface of the cancer cell line of protein resistance, can be attached to the toxin or radiolabel and then combined to cause cellular antibodies The human immobilization zone is treated to cause apoptosis or death by binding the antibody to the body effector mechanism. One of the antibodies to treat moderate and high lymphocytes is lethal 8 1280137. V. Description (2) (0ncolyra@) ((3) i-Lym-1) (Technical Cloning Company (Ding echnicl〇ne Corp.), which is A murine IgG2a monoclonal antibody that recognizes HLA-DrlO protein on the surface of more than 80% of lymphoma cells. Only 2% of normal b cells (non-cancerous) exhibit HLA-D r 1 0 molecules. Broken-[Mi] (131 I ), the radioactive isotope of iodine emits a few hundred millimeters of stone radiation' and thus it is considered to be a valid target for the outer edge of the tumor and can stop the continuation of the giant disease. The potential disadvantage of Hodgkin's lymphoma with the use of lethality is that such lymphoma often has the characteristics of bone marrow inclusion. Therefore, administration of radiolabeled antibodies to such patients often causes undesirable bone marrow suppression and Healthy primordial cells cause damage. It would be excellent if there were additional treatments and other monoclonal antibodies that could be administered to patients with intermediate and southern lymphoma to avoid the disadvantages associated with current treatments and reduce recurrence rates. Summary of invention The present invention relates to the use of anti-CD20 antibodies for the treatment of moderate and high-grade lymphomas, particularly those with bone marrow inclusion and megasis. In particular, the inventors have unexpectedly discovered that they have been approved for the treatment of mild glands. The chimeric anti-gas 020 antibody Rissus Moss (1^1; 11 to 11^13®^) of the non-Hodgkin's lymphoma can effectively treat the more aggressive lymphoma. A method for treating or ameliorating moderate or high non-Hodgkin's lymph, or other lymphoma sign associated with high bone marrow inclusion, = including administering a therapeutically effective amount of an anti-CD20 antibody or other ground-breaking to a patient ,

1280137 V. INSTRUCTIONS (3) Antibodies to lymphoma cells, such as anti-C D1 9 and anti-C D 2 2 antibodies, or therapeutically effective fragments thereof. The invention also includes administering a drug anti-CD2〇 antibody, or other antibody that destroys lymphoma cells, as part of a transplantation therapy (autologous bone transplantation or allogeneic bone marrow transplantation or peripheral blood stem cell transplantation) to improve the transplanted person. Survive. A therapeutically effective antibody ''fragment') means when any part or derivative of an antibody is administered to a patient with moderate or high non-Hodgkin's lymphoma (NHL)' or when used in a In the case of transplantation therapy, it can deliver almost the same therapeutic effect as a complete antibody. Due to the diagnosis of lymphoma and the variation of histopathology, a new classification system for different types of lymphoma appears. For the methods described herein, moderate and high-grade lymphomas are confined to 1 982 apricots with a large penalty for immunoblasts & TDτ, 斤 辨 4 冋 淋巴 淋巴 及, and small =; = (IBLV Shaped or non-returned Lymphatics (SNC). Knife, 肊, ki, (Brazil tt, S) or non-bow from the practical formula proposed de + near by European and American pathologists have several classifications For example, the most (REAL) taxonomy. Although the yarn is "excepted," the term is called the revised European and American lymphoma NHL, but "the second class does not use moderate". "Height, the characteristics of lymphoma. Example dip" "This artist should know π Moderate, and,, and height, "lymphoma" may appear as defined in the 'REAL classification system'. The coat cells are painless and more aggressive, and rely on severe 1280137. 4) One sex can be classified as moderate or high lymphoma. For example, the National Cancer Center (NCI) has sequentially classified certain REAL categories into more clinically useful "painless" or, "aggressive" lymphoma names. "Attacking f' lymphoma including disseminated mixed and large cell lymphoma, Bausch's lymphoma/distributed small non-dividing cell lymphoma, lymphoblastic lymphoma, mantle cell lymphoma, and lymphoid associated with A丨DS Thus, such lymphomas are considered to be at least "moderate," or "highly", and they would benefit from the treatment of the present invention. Strict classification of certain lymphomas can be extremely difficult, but can be treated by the present invention. Lymphoma is generally characterized by a large number of circulating B cells, which may be bone marrow-containing, giant, or extra-lymphatic organs or regions. Patients who are generally best served by the disclosed treatments It means that it is difficult to be cured by other types of treatments, or it is relapsed in other types of treatments, such as chemotherapy or radiation therapy. However, the monoclonal antibody treatment disclosed in the present invention will also benefit new diagnosed patients. And if combined with other conventional therapies, there may be a synergistic effect to reduce the chance of recurrence. For example, the method of the present invention includes administering a monoclonal antibody (or a fragment thereof) of CD2〇 and chemotherapy, depending on individual patients. The chemotherapeutic treatment can be administered together or sequentially in any order. "Common" means simultaneously or within the same time period to overlap the circulating half-life of the therapeutic agent. Chemoscings that can be combined with the antibody therapies of the invention include CH〇p, ICE , Mitozantrone, Cytarabine, DVP, ATRA, idarubicin, hoelzer chemotherapeutic, La La chemotherapeutic, ABVD , CE0P, 2-CdA,

1280137 V. INSTRUCTIONS (7) 'Therefore, it was chosen as a radionuclide for diagnosis. Patents relating to chelate and chelate combinations are known in the art. For example, U.S. Patent No. 4,831,175 to Gansow, which is incorporated herein by reference. U.S. Patent Nos. 5,099,069, 5,246,692, 5,286,850, and 5,124,471 are also incorporated herein by reference. These patents are incorporated herein by reference in their entirety. The specific bifunctional chelates selected for use in promoting chelation in applications 08/475, 813, 08/475, 815 and 08/478,967 are due to their high affinity for trivalent metals and increase tumors. For the ratio of non-tumor, reduce the absorption of the bone and the 'radio nucleus in the living body, that is, the B cell lymphoma tumor increases the retention. However, other bifunctional meal products known in the art may also be beneficial for tumor treatment. The σ application 08/475, 8 1 3, 08/475, 8 1 5 and 08/478, 967 also disclose radiolabeled therapeutic antibodies for use in and destruction of beta cell lymphoma and tumor cells. In particular, the Υ2Β8 conjugate comprises the same anti-human CD2 squirrel monoclonal antibody 2β8 linked to 钇-[90] (9〇Υ) via the same bifunctional chelating compound. This radionuclear factor was chosen for therapeutic reasons. The 64-hour half-life of 9 〇 γ = to cause the tumor to accumulate antibodies, and does not resemble, for example, 1311, which is pure y this stone emitter and does not accompany 100 to 100 when it decays. Cell diameter. The lowest penetration is m ^90 Λ / ^ The edging of the teeth allows the outpatients to have ‘Y_彳* 3 antibodies. In addition, killing cockroaches, internalizing, and locally emitting ionized radiation "Asian: the labeled antibody near tumor cells have a lethal effect. Ray response to the lack of the target antigen

Page 10 1280137 V. Description of the invention (8) Because the 9G Y radionuclide is the same double 妫Attown ^ ^ η , νοη and the integrator molecule MX-DTPA are connected to the 2B8 anti-limb, therefore, the Y2B8 combination body The same advantages as described above, for example, increase the π retention of the m-glycine core at the target (tumor). However, it does not resemble the 111 In 2//" system" and can not be used to produce images. Therefore, the radionucleus of the image, such as 1111, can be used first to determine the tumor: set relative size and / or again Administration of anti-synthesis or sputum-labeled anti-synthesis therapy of the present invention. In addition, indium-labeled antibodies can be used for the analysis of dosimetry. Knowing the use of k-body, that is, as a diagnostic agent or treatment Agents, there are other known radiolabels in this art and have been used for the same purpose. For example, the radionuclides that have been used in the diagnosis of 6-bed include 131 I, 1251, 1231, 99Tc, Ga, and 111 In. Labeled by a variety of radionuclides for effective immunotherapy (Pierersz et al. (1 987) monoclonal antibody conjugates for the diagnosis and treatment of cancer. Immun 〇 1, CeU Bi 〇 1. 65 : 1 1 1 - 1 25 ). Such radionuclides include (8). *186Re and 9()丫, and less used 199Au and 67Cu. U.S. Patent Nos. 5, 46, 785 lists such radioisotopes and Incorporating this document for reference. For example, in the case of Common Towels 08/475, 813, 08/475, 815 and 08/478, 967 The results of the 'yield radiolabeled γ2Β8 conjugate and the unlabeled chimeric anti-CD2 0 antibody (Ritasimo ©) resulted in a significant reduction in tumors in the latent β-cell lymphoma tumors. Human clinical trials have shown that injection of Ritrasmo® in mild sputum lymphoma significantly eliminates sputum cells. In fact, RITOSMO® was recently predicted to be the country's first FDA-approved anti-cancer monoclonal antibody.

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In addition, the U.S. Application Serial No. 8/475, 8 1 3, which is incorporated herein by reference, is incorporated by reference. The drug rittastatin 8, chimeric type, 2 〇, and either the indium label or the eclipse, the murine early strain antibody, or one of them to treat mild NHL. Although the radiolabeled antibody used in the combination therapy is a murine antibody, the sputum type 杬-CD20 is initially used to sufficiently eliminate the B cell population to lower the HAM response, thereby promoting the combination therapy and diagnostic therapy. Even, U.S. Application Serial No. 08/475, 801 shows that an effective amount of a sputum-labeled anti-CD2 sputum antibody is administered first, followed by rittasmore® (a) to remove any unchimeric resistance. - remaining peripheral blood B cells by CD20 antibody clearance; (b) B cells that begin to eliminate lymph nodes; or (c) B cells that begin to eliminate other tissues. In general, autologous bone marrow transplantation is a successful concomitant treatment of bone marrow erosion, which helps patients who have received radiation therapy or chemotherapy to restore the immune system. However, as mentioned above, lymphomas suffering from patients benefiting from the methods described herein are often accompanied by bone marrow inclusion. Such patients often contain a large number of cancer cells in the bone marrow and cannot be autografted. When a moderate or high-grade lymphoma is accompanied by bone marrow inclusion, the patient is eligible for treatment with human, chimeric or human-like anti-CD2〇 antibody to reduce tumor cells in bone marrow or stem cell preparation before collecting bone marrow. The content. In fact, the administration of Resimo® can improve the survival rate of transplant recipients during the induction period, in vivo cleansing period, fluid phase, modulating period, re-injection after transplantation, and any other time of bone marrow or stem cell transplantation. , the induction period, means the beginning of treatment, the purpose of which is to achieve induction of the reduction of the condition. The general induction period involves the administration of certain types of chemotherapy, also known as CHOP. The term 'living cleansing period' means the & therapy, especially the removal of patients, internal bone marrow

Page 12 1280137 V. INSTRUCTIONS (10) Swollen: cells, although this treatment may be 35 for peripheral blood and its a: tumor cells. Because of the reduction in the number of tumor cells? Part 2: Step: Collect bone marrow. In this regard, Ritas Mosquito and Λ 口 ^• lymphoma cell elimination antibody provides 俨, 匕: because it can be used to clear the cancer cells without destruction; Leave the bone marrow and provide a source of stem cells for another type of transplant outside the bone marrow collection. ! First, the (four) agent and / or growth factor to get the flow V voter =:::= TG-CSF, but according to the acquaintance of this artist's account • 1 period is to separate stem cells from the blood (and then put the liquid Back to the disease j body), and then the stem cells are cold-bundled until the patient is ready to re-injection. The process can be used by Rismusmo® or other techniques that can be used in this--------- / "Smoke He" stands for extra limb clearance to remove tumor cells 0 vT# ie ' #思曰病 Ready to receive autologous bone marrow reinjection or allograft / It Γ陆二& with very high dose Chemotherapy removes healthy cells from the bone marrow. A chemotherapeutic agent known in the art to give a sufficiently high dose without jeopardizing the life of the patient is, for example, cyclophosphamide. 4 Ritras at different stages of transplantation In the treatment of Momo®, the epiphysis can be collected before the osteophyte invasive treatment, and then added to the treatment in order, and the tumor cells in the original collected bone marrow are added to the patient's body and the heart is Or by radiolabeling antibodies,

1280137 V. Description of invention (11) Such as Y 2 B 8 to further reduce the chance of recurrence. Human methods of the invention also include combination therapies and include administration of at least one tissue and anti-CD20 antibody or fragment thereof. The interleukin can be administered simultaneously or in any order. In particular, the interleukin is administered — CD2〇 antibodies can be used to modulate the appearance of cancerous B cells (3). The interleukins that can be used for this purpose include IL-4, GM-CSF and TNF-α, among others. The interleukin can also be administered simultaneously or at the same time to increase or control certain effector functions modulated by the therapeutic antibody. The mediators that can be used for this purpose include interferon alpha, G-csf and GM_CSF, and others. Preferred methods of administration and specific examples as examples will now be illustrated by the following data. j: One drug was studied in Europe and Australia, and the drug list was evaluated in 54 relapsed or difficult to treat moderate or southern NHL patients (c〇if f ier B) Haioun C 'Ketterer Ν, Engert A, Tilly η, Ma (D), Johnson (Lister) A ' fee Feuring-Buske M, Radford JA, Capdeville R, Diehl V 'Reyes F. Rismusmo - CD2 〇 monoclonal antibody) for patients with relapsed or difficult to treat aggressive lymphoma · Multi-center facial paralysis study. Blood 1 998 ; 92:1 9 27 -1 932 ). The injection of Ritrasmo® is 8 doses per week or 375 mg/m2 at 375 mg/m2 followed by 7 doses of 50 mg/m2 per week. 〇RR was 31%; (CR 9%, PR 22%) No significant differences were observed between medications. Suffering from spreading

Page 14 1280137 V. INSTRUCTIONS (12) The 〇RR of large cell lymphoma patients (N = 3〇) was 37%, and the 0RR of patients with mantle cell lymphoma (N = 12) was 33%. The treatment of giant disease and early hypothesis antibody treatment can only be used in the opposite of micrometastasis, and Rismusmo® is quite active in the southern giant disease. In a separate study, 3 i patients with relapsed or refractory, giant mild NHL (single tumor of diameter > 1 cm) received 375 mg/m 2 ristasimo for four weeks. Twelve (43%) of the 28 evaluable patients showed CR (1,4%) or PR (11, 39%) (Davis T, White C, Gurley Grillo-L6pez A, Velasquez w, Link B 'Maloney D, Dillman R, Williams Μ , Mohrbacher a, Weaver R, Dowden S, Levy R. Rismusmo: The first NHL patient (pts) with giant disease Phase (PI丨) first report. Blood 1998; 92 (10 supplements i): 4i4a. This indicates that the appropriate dose is the number of tumor cells depending on the extent of the disease and circulation (ie, for example, the above-mentioned increased dose), Ritta Smo® can also be used for more aggressive moderate or high-level NHLs with giant disease. Combination of Rismusmo @ ACHOP 痪 Another study, 31 patients with moderate or high NHL ( 19 women, 12 men, with a median age of 49) Received Rismusmo® (Link B, Grossbard) on each of the first 21 days of CHOP in six 21-day cycles ) Hey, Fisher R G If Mann (czuczman)

Hey, Gilman P, Lowe A, Vose J. Chapter II

Page 15 1280137 V. INSTRUCTIONS (13) Phase Experimental Study of the safety and efficacy of a combination of rivasmo and CHOP chemotherapy in patients with previously untreated or moderate NHL. Journal of the American Society of Clinical Oncology 1 9 98 ; 17:3a). Of the 30 evaluable patients, 96% (6 3 %) and 1 〇 p R (33%) were found in 96% of 0RR. This therapy is considered to be extremely tolerant and results in a higher response rate than Ritrasmo or CHOP alone.

The NCI department for cancer treatment and diagnosis works with IDEC Pharmaceuticals to develop a treatment for other symptoms in the status. CHOP's Phase 11 trial of CHOP and Resimo® is performed by EC0G, CALGB, and SW0G in older patients (>60 years old) on large cell tissue NHLs that mix, disperse large cells, and immunoblasts. (Plan N = 630). This study includes any alternatives to Rismusmo @Protection for unprotected. The ITS I Rismo and CHOP trials were also performed at the Dana Fabr e Center for patients with previously untreated, mantle cell lymphoma. On the first day of the 21st day, Ressex® was administered and CHOP was administered on the 3rd day for 6 cycles. The results of this study have been collected. From sw〇G, CHOP, a newly diagnosed acinar lymphoma, followed by Ritusmo's 丨 丨 stage " 13⁄4 has also been formed. The results of these two experiments have been analyzed.

The second phase of the trial of CHOP and Rismusmo vs. CH〇p alone in 盥HIv, the NHL was performed by the AIDS Malignant Tumor Alliance; there are plans for 12 patients. A mi·sheng treatment of recurrence, Rismus Mobi must be a high-dose treatment with autologous PBSC, showing promising initial results in patients with recurrent moderate fox. Two patients responded (1 CR and 5 PR) and one patient had stable disease; the treatment was excellent (Tsai), D, M〇〇re H, Porter...

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Claims (1)

1280137 Case No. 89116248 Patent Application No. 1. A pharmaceutical composition for treating or alleviating moderate or high non-Hodgkin's lymphoma symptoms in a patient, comprising a therapeutically effective amount of an anti-CD 20 antibody or therapeutically effective thereof A fragment of the amount wherein the antibody is a human, chimeric or humanized antibody. 2. The pharmaceutical composition according to claim 1, wherein the non-Hodgkin's lymphoma is selected from a large acinar cell (FL), a small dividing cell (DSC), and a small mixed large and large cell (D) Μ ), dissemination of large dividing cells (DL-C), dissemination of non-dividing large cells (DL), large cells of immunoblasts (IBL), anaplastic lymphocytes (LL-C), non-transgenic lymphoblasts ( LL), small non-dividing cells - Burkitt's (SNC-Β), small non-dividing cells - non-Bow's (SNC), mantle cell lymphoma, and AIDS-related lymphoma . Wherein the patient is the patient, wherein the patient, the patient, the patient, and the chemotherapy 3. The pharmaceutical composition according to the second application of the patent scope, Chikin's lymphoma is accompanied by a giant disease. 4. Pharmaceutical compositions according to item 1 of the scope of the patent application are difficult to treat by other treatments. 5. The pharmaceutical composition according to item 4 of the patent application is difficult to be treated by chemotherapy or radiation therapy. 6. The pharmaceutical composition according to claim 1 of the patent application relapsed after prior treatment with non-Hodgkin's lymphoma. 7. The pharmaceutical composition according to claim 6 of the patent application recurs after chemotherapy or radiation therapy. 8. The pharmaceutical composition method according to claim 1 of the patent application is combined and administered to the patient. O:\65\65715-951215.ptc Page 19 1280137 _ Case No. 89116248_Yearly Revision _ VI. Patent Application Scope 9. Pharmaceutical compositions according to item 8 of the scope of application, which are simultaneously or in any order Chemotherapy is administered sequentially. I 0. The pharmaceutical composition according to claim 9 of the patent application, wherein the chemotherapeutic method is selected from the group consisting of CHOP, ICE, Mitozantrone, Cyta tarabine, DVP, ATRA, Ada Idarubicin, Hoelzer Chemotherapy, La La Chemotherapy, Human 3乂0, 0£0?, 2-0 (1 person, 卩1^6 and 10 people) (with or without G-CSF treatment), VAD, sputum and P, weekly C, ABCM, ΡΡ0ΡΡ, and DHAP. II. Pharmaceutical composition according to claim 10, The chemotherapeutic method is CHOP. 1 2. The pharmaceutical composition according to claim 1, wherein the chimeric antibody is rituximab. 1 3. Medicine according to claim 1 a composition which is administered in combination with a radiolabeled antibody which binds to a protein on the surface of a cancerous B cell. The pharmaceutical composition according to claim 13 wherein the radiolabeled antibody is Anti-CD20 antibody. 1 5. The pharmaceutical composition according to claim 14 of the patent application, wherein The antibody is Y2B8. The pharmaceutical composition according to claim 1, wherein the moderate or high lymphoma is accompanied by bone marrow inclusion. 1 7. The pharmaceutical composition according to claim 16 of the patent application, It is transplanted with bone marrow or stem cells. O:\65\65715-951215.ptc Page 20 1280137 _ Case No. 89116248 November 曰 Amendment _ VI. Patent Application Range 18. The pharmaceutical composition according to Article 17 of the patent application scope, which is self-contained Transplant the bone or stem cells. The pharmaceutical composition according to claim 18, wherein the patient is treated with a chimeric anti-CD20 antibody before and/or following the collection or transplantation of bone marrow or stem cells. The pharmaceutical composition according to claim 16 wherein the antibody is a chimeric anti-CD20 antibody. The pharmaceutical composition according to claim 20, wherein after the chimeric anti-CD20 antibody is administered, a radiolabeled antibody is additionally administered. The pharmaceutical composition according to claim 21, wherein the antibody is an anti-CD20 antibody. The pharmaceutical composition according to claim 22, wherein the antibody is Y2B8. 2. The pharmaceutical composition according to claim 1, further comprising at least one interleukin. The pharmaceutical composition according to claim 1, wherein the interleukin is administered prior to the anti-CD 20 antibody to modulate the expression of CD20 on the surface of cancerous B cells. The pharmaceutical composition according to claim 24, wherein the composition is selected from the group consisting of interferon alpha, G-CSF and GM-CSF. The pharmaceutical composition according to claim 25, wherein the group of interleukins is selected from the group consisting of IL-4, GM-CSF and TNF-α. The pharmaceutical composition according to claim 18, wherein the anti-C D 2 0 antibody is administered to the disease during the induction period of bone marrow or stem cell transplantation O:\65\65715-951215.ptc Page 21 1280137 _ Case No. 89116248_f Year Month Day Amendment _ VI. Patent Application Scope. The pharmaceutical composition according to claim 18, wherein the anti-CD20 antibody is administered to the patient during the in vivo cleansing period of the bone marrow or stem cell transplantation method. The pharmaceutical composition according to claim 18, wherein the anti-CD20 antibody is administered to the patient during a flow period of bone marrow or stem cell transplantation. The pharmaceutical composition according to claim 18, wherein the anti-CD20 antibody is administered to the patient during a modulating phase of bone marrow or stem cell transplantation. 3. The pharmaceutical composition according to claim 18, wherein the anti-CD20 antibody is administered to the patient during the reinjection period after transplantation of the bone marrow or stem cell transplantation method. 3. The pharmaceutical composition according to claim 18, wherein the anti-CD20 antibody is administered to the patient as part of a post-transplant protection method. 3. The pharmaceutical composition according to claim 2, wherein the non-Hodgkin's lymphoma is selected from the group consisting of a large dividing cell (DL-C) and a non-dividing large cell (DL). . O:\65\65715-951215.ptc Page 22