WO2010061357A1 - Antitumor combinations containing antibodies recognizing specifically cd38 and melphalan - Google Patents

Antitumor combinations containing antibodies recognizing specifically cd38 and melphalan Download PDF

Info

Publication number
WO2010061357A1
WO2010061357A1 PCT/IB2009/055389 IB2009055389W WO2010061357A1 WO 2010061357 A1 WO2010061357 A1 WO 2010061357A1 IB 2009055389 W IB2009055389 W IB 2009055389W WO 2010061357 A1 WO2010061357 A1 WO 2010061357A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
amino acid
nos
antibody
light chain
Prior art date
Application number
PCT/IB2009/055389
Other languages
French (fr)
Inventor
Pascale Lejeune
Patricia Vrignaud
Original Assignee
Sanofi-Aventis
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=40578382&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2010061357(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to KR1020117014746A priority Critical patent/KR101733252B1/en
Priority to EP09775302A priority patent/EP2370094A1/en
Priority to MX2011005670A priority patent/MX342625B/en
Priority to SG2011037967A priority patent/SG171820A1/en
Priority to AU2009321249A priority patent/AU2009321249B2/en
Priority to CN200980148094.4A priority patent/CN102264385B/en
Priority to UAA201108006A priority patent/UA107069C2/en
Priority to CA2744990A priority patent/CA2744990C/en
Priority to MEP-2011-93A priority patent/ME01136B/en
Application filed by Sanofi-Aventis filed Critical Sanofi-Aventis
Priority to NZ593027A priority patent/NZ593027A/en
Priority to EA201100864A priority patent/EA026867B1/en
Priority to US13/130,862 priority patent/US9259406B2/en
Priority to BRPI0921864-5A priority patent/BRPI0921864B1/en
Priority to JP2011538092A priority patent/JP2012510461A/en
Publication of WO2010061357A1 publication Critical patent/WO2010061357A1/en
Priority to TN2011000232A priority patent/TN2011000232A1/en
Priority to IL213116A priority patent/IL213116B/en
Priority to ZA2011/03925A priority patent/ZA201103925B/en
Priority to MA33937A priority patent/MA32896B1/en
Priority to HK12105154.7A priority patent/HK1164165A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Antitumor combinations containing antibodies recognizing specifically CD38 and melphalan are included in the composition.
  • the present invention relates to combinations of monoclonal antibodies directed against CD38 and melphalan which are therapeutically useful in the treatment of neoplastic diseases.
  • CD38 is a 45 kD type Il transmembrane glycoprotein with a long C-terminal extracellular domain and a short N-terminal cytoplasmic domain.
  • the CD38 protein is a bifunctional ectoenzyme that can catalyze the conversion of NAD + into cyclic ADP- ribose (cADPR) and also hydrolyze cADPR into ADP-ribose.
  • cADPR cyclic ADP- ribose
  • CD38 is upregulated and has been implicated in many hematopoietic malignancies.
  • Monoclonal antibodies 38SB13, 38SB18, 38SB19, 38SB30, 38SB31 , and 38SB39, which specifically recognize CD38, are described in PCT application WO2008/047242.
  • Said anti-CD38 antibodies are capable of killing CD38 + cells by three different cytotoxic mechanisms, induction of apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC).
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • CDC complement-dependent cytotoxicity
  • these antibodies are able to directly induce apoptosis of CD38 + cells, even without the presence of stroma cells or stroma-derived cytokines.
  • Melphalan is an alkylating agent used in chemotherapy. Nevertheless, there is still a need for new and efficacious medicaments for treating cancer.
  • the efficacy of the humanized anti- CD38 antibodies may be considerably improved when it is administered in combination with at least one substance which is therapeutically useful in anticancer treatments and has a mechanism identical to or different from the one of the humanized anti-CD38 antibodies and which is limited in the present invention to melphalan.
  • antibody is used herein in the broadest sense and specifically covers monoclonal antibodies (including full length monoclonal antibodies) of any isotype such as IgG, IgM, IgA, IgD and IgE, polyclonal antibodies, multispecific antibodies, chimeric antibodies, and antibody fragments.
  • a typical IgG antibody is comprised of two identical heavy chains and two identical light chains that are joined by disulfide bonds. Each heavy and light chain contains a constant region and a variable region. Each variable region contains three segments called “complementarity-determining regions" ("CDRs") or “hypervariable regions", which are primarily responsible for binding an epitope of an antigen. They are usually referred to as CDR1 , CDR2, and CDR3, numbered sequentially from the N-terminus. The more highly conserved portions of the variable regions outside of the CDRs are called the "framework regions”.
  • CDRs complementarity-determining regions
  • V H or "VH” refers to the variable region of an immunoglobulin heavy chain of an antibody, including the heavy chain of an Fv, scFv, dsFv, Fab, Fab' or F(ab')2 fragment.
  • V L or “VL” refers to the variable region of the immunoglobulin light chain of an antibody, including the light chain of an Fv, scFv, dsFv, Fab, Fab' or F(ab')2 fragment.
  • the 38SB13 antibody comprises at least one heavy chain having an amino acid sequence consisting of SEQ ID NO: 50 and at least one light chain having an amino acid sequence consisting of SEQ ID NO: 38, said heavy chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 1 , 2, and 3, and said light chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 4, 5, and 6.
  • the 38SB18 antibody comprises at least one heavy chain having an amino acid sequence consisting of SEQ ID NO: 52 and at least one light chain having an amino acid sequence consisting of SEQ ID NO: 40, said heavy chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 7, 8, and 9, and said light chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 10, 11 , and 12.
  • the 38SB19 antibody comprises at least one heavy chain having an amino acid sequence consisting of SEQ ID NO: 54 and at least one light chain having an amino acid sequence consisting of SEQ ID NO: 42, said heavy chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 13, 14, and 15, and said light chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 16, 17, and 18.
  • the 38SB30 antibody comprises at least one heavy chain having an amino acid sequence consisting of SEQ ID NO: 56 and at least one light chain having an amino acid sequence consisting of SEQ ID NO: 44, said heavy chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 19, 20, and 21 , and said light chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 22, 23, and 24.
  • the 38SB31 antibody comprises at least one heavy chain having an amino acid sequence consisting of SEQ ID NO: 58 and at least one light chain having an amino acid sequence consisting of SEQ ID NO: 46, said heavy chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 25, 26, and 27, and said light chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 28, 29, and 30.
  • the 38SB39 antibody comprises at least one heavy chain having an amino acid sequence consisting of SEQ ID NO: 60 and at least one light chain having an amino acid sequence consisting of SEQ ID NO: 48, said heavy chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 31 , 32, and 33, and said light chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 34, 35, and 36.
  • hybridoma cell lines producing the 38SB13, 38SB18, 38SB19, 38SB30, 38SB31 , and 38SB39 murine anti-CD38 antibodies have been deposited at the American Type Culture Collection (10801 University Bid, Manassas, VA, 201 10-2209, USA), on June 21 , 2006, under the deposit numbers PTA-7667, PTA-7669, PTA-7670, PTA-7666, PTA-7668, and PTA-7671 , respectively (as described in WO2008/047242).
  • humanized antibody refers to a chimeric antibody which contain minimal sequence derived from non-human immunoglobulin.
  • the goal of humanization is a reduction in the immunogenicity of a xenogenic antibody, such as a murine antibody, for introduction into a human, while maintaining the full antigen binding affinity and specificity of the antibody.
  • Humanized antibodies, or antibodies adapted for non-rejection by other mammals may be produced using several technologies such as resurfacing and CDR grafting.
  • the resurfacing technology uses a combination of molecular modelling, statistical analysis and mutagenesis to alter the non-CDR surfaces of antibody variable regions to resemble the surfaces of known antibodies of the target host.
  • the CDR grafting technology involves substituting the complementarity determining regions of, for example, a mouse antibody, into a human framework domain, e.g., see WO 92/22653.
  • Humanized chimeric antibodies preferably have constant regions and variable regions other than the complementarity determining regions (CDRs) derived substantially or exclusively from the corresponding human antibody regions and CDRs derived substantially or exclusively from a mammal other than a human.
  • Antibodies can be humanized using a variety of other techniques including CDR-grafting (EP 0 239 400; WO 91/09967; U.S. Pat. Nos. 5,530,101 ; and 5,585,089), veneering or resurfacing (EP 0 592 106; EP 0 519 596; Padlan E. A., 1991 , Molecular Immunology 28(4/5): 489-498; Studnicka G. M. et al., 1994, Protein Engineering, 7(6): 805-814; Roguska M.A.
  • Human antibodies can be made by a variety of methods known in the art including phage display methods. See also U.S. Pat. Nos. 4,444,887, 4,716,111 , 5,545,806, and
  • the anti-CD38 antibodies of the pharmaceutical combination of the present invention are humanized antibodies which recognize CD38 and kill CD38 + cells by apoptosis, ADCC, and CDC.
  • the humanized antibodies of the invention are capable of killing said CD38 + cells by apoptosis even in the absence of stroma cells or stroma-derived cytokines.
  • a preferred embodiment of such a humanized antibody is a humanized 38SB13, 38SB18, 38SB19, 38SB30, 38SB31 , or 38SB39 antibody, or an epitope-binding fragment thereof.
  • this invention provides humanized antibodies or epitope-binding fragment thereof comprising one or more CDRs having an amino acid sequence selected from the group consisting of SEQ ID NOS: 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, and 36.
  • a humanized version of 38SB13 which comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 1 , 2, and 3, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 4, 5, and 6.
  • a humanized version of 38SB18 which comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 7, 8, and 9, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 10, 11 , and 12.
  • a humanized version of 38SB19 which comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity- determining regions having amino acid sequences represented by SEQ ID NOS: 13, 14, and 15, and wherein said light chain comprises three sequential complementarity- determining regions having amino acid sequences represented by SEQ ID NOS: 16, 17, and 18.
  • a humanized version of 38SB30 which comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 19, 20, and 21 , and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 22, 23, and 24.
  • a humanized version of 38SB31 which comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 25, 26, and 27, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 28, 29, and 30.
  • a humanized version of 38SB39 which comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 31 , 32, and 33, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 34, 35, and 36.
  • this invention provides humanized antibodies or fragments thereof which comprise a V H having an amino acid sequence selected from the group of SEQ ID NOS: 66 and 72.
  • a humanized 38SB19 antibody is provided which comprises a V H having an amino acid sequence represented by SEQ ID NO: 66.
  • a humanized 38SB31 antibody is provided which comprises a V H having an amino acid sequence represented by SEQ ID NO: 72.
  • this invention provides humanized antibodies or fragments thereof which comprise a V L having an amino acid sequence selected from the group of SEQ ID NOS: 62, 64, 68, and 70.
  • a humanized 38SB19 antibody is provided which comprises a V L having an amino acid sequence chosen from the group of SEQ ID NOS: 62 and 64.
  • a humanized 38SB31 antibody is provided which comprises a V L having an amino acid sequence chosen from the group of SEQ ID NOS: 68 and 70.
  • each of the humanized versions of the 38SB13, 38SB18, 38SB19, 38SB30, 38SB31 , and 38SB39 antibodies has been shown to be particularly advantageous as an anticancer agent.
  • the preparation, physical properties and beneficial pharmacological properties thereof are described in WO 2008/047242, which is incorporated by reference herein in its entirety.
  • the doses used for treating human beings are between 1 and 150 mg/kg administered orally or between 1 and 150 mg/kg administered intravenously.
  • Melphalan (brand name, AlkeranTM), is a chemotherapy drug belonging to the class of nitrogen mustard alkylating agents. Otherwise known as L-Phenylalanine Mustard, or L-PAM, melphalan is a phenylalanine derivative of mechlorethamine and is a bifunctional alkylating agent. Formation of carbonium intermediates from each of the two bis-2-chloroethyl groups enables alkylation through covalent binding with the 7- nitrogen of guanine on DNA, cross-linking two DNA strands and thereby preventing cell replication. Melphalan is used primarily to treat multiple myeloma and ovarian cancer, and occasionally malignant melanoma. It is usually administered orally or intravenously.
  • One aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising an anti-CD38 antibody in combination with at least melphalan. Since the activity of the products depends on the doses used, it is thus possible to use lower doses and to increase the activity while decreasing the toxicity phenomena.
  • the improved efficacy of a combination according to the invention may be demonstrated by determination of the therapeutic synergy.
  • a combination manifests therapeutic synergy if it is therapeutically superior to the best agent of the study used alone at its maximum tolerated dose or at its highest dose tested when toxicity cannot be reached in the animal species.
  • logTM cells kill which is determined according to the following formula:
  • T - C represents the tumor growth delay, which is the median time in days for the tumors of the treated group (T) and the tumors of the control group (C) to reach a predetermined value (1 g for example), and T d represents the time in days needed for the volume of the tumor to double in the control animals [T. H. Corbett et al., Cancer, 40: 2660-2680 (1977); F. M. Schabel et al., Cancer Drug Development, Part B, Methods in Cancer Research, 17: 3-51 , New York, Academic Press Inc. (1979)].
  • a product is considered to be active if logTM cell kill is greater than or equal to 0.7.
  • a product is considered to be very active if logTM cell kill is greater than 2.8.
  • the combination will manifest therapeutic synergy when the logTM cell kill is greater than the value of the logTM cell kill of the best constituent when it is administered alone and used at its maximum tolerated dose or at its highest dose tested.
  • the efficacy of the combinations on solid tumors may be determined experimentally in the following manner:
  • mice The animals subjected to the experiment, generally mice, are subcutaneously grafted bilaterally with 30 to 60 mg of a tumor fragment on day 0.
  • the animals bearing tumors are randomized based on their tumor size before being subjected to the various treatments and controls.
  • Chemotherapy begins when tumors have reached a predetermined size after grafting, depending on the type of tumor, and the animals are observed every day.
  • the different animal groups are weighed daily during treatment until the maximum weight loss is reached and subsequent full weight recovery has occurred.
  • the groups are then weighed once or twice a week until the end of the trial.
  • the tumors are measured 1 to 5 times a week, depending on the tumor doubling time, until the tumor reaches approximately 2 g, or until the animal dies (if this occurs before the tumor reaches 2 g).
  • the animals are necropsied immediately after euthanasia or death.
  • the antitumor activity is determined in accordance with the different parameters recorded.
  • the present invention also relates, therefore, to pharmaceutical compositions containing the combinations according to the invention.
  • the constituents of which the combination are composed may be administered simultaneously, semi-simultaneously, separately, or spaced out over a period of time so as to obtain the maximum efficacy of the combination; it being possible for each administration to vary in its duration from a rapid administration to a continuous perfusion.
  • the combinations are not exclusively limited to those which are obtained by physical association of the constituents, but also to those which permit a separate administration, which can be simultaneous or spaced out over a period of time.
  • compositions according to the invention are preferably compositions which can be administered parentally. However, these compositions may be administered orally, subcutaneously or intraperitoneal ⁇ in the case of localized regional therapies.
  • compositions for parental administration are generally pharmaceutically acceptable, sterile solutions or suspensions which may optionally be prepared as required at the time of use.
  • natural vegetable oils such as olive oil, sesame oil or liquid petroleum or injectable organic esters such as ethyl oleate may be used.
  • the sterile aqueous solutions can consist of a solution of the product in water.
  • the aqueous solutions are suitable for intravenous administration provided the pH is appropriately adjusted and the solution is made isotonic, for example with a sufficient amount of sodium chloride or glucose.
  • the sterilization may be carried out by heating or by any other means which does not adversely affect the composition.
  • the combinations may also take the form of liposomes or the form of an association with carriers as cyclodextrins or polyethylene glycols.
  • compositions for oral, subcutaneous or intraperitoneal administration are preferably aqueous suspensions or solutions.
  • the application of the constituents of which may be simultaneous, separate or spaced out over a period of time it is especially advantageous for the amount of humanized anti-CD38 antibody to represent from 10 to 90 % by weight of the combination, it being possible for this content to vary in accordance with the nature of the associated substance, the efficacy sought and the nature of the cancer to be treated.
  • carcinomas and adenocarcinomas including that of the bladder, breast, colon, head-and-neck, prostate, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin, and including squamous cell carcinoma ; hematopoietic tumors of lymphoid lineage, including multiple myeloma, leukemia, acute and chronic lymphocytic (or lymphoid) leukemia, acute and chronic lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, non- Hodgkin lymphoma (e.g.
  • Burkitt's lymphoma Burkitt's lymphoma
  • hematopoietic tumors of myeloid lineage including acute and chronic myelogenous (myeloid or myelocytic) leukemias, and promyelocytic leukemia
  • tumors of mesenchymal origin including fibrosarcoma, osteosarcoma and rhabdomyosarcoma
  • tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma, and schwannomas
  • other tumors including melanoma, teratocarcinoma, xeroderma pigmentosum, keratoacanthoma, and seminoma, and other cancers yet to be determined in which CD38 is expressed.
  • They are mainly useful for treating leukemia, lymphoma and cancers resistant to the commonly used anticancer agents as the anti-CD38 antibodies of the invention have a unique mechanism of action.
  • the invention also encompasses the use of the above combinations for the manufacture of a medicament for the treatment of cancer.
  • the first selected tumor model was a transplantable human multiple myeloma cell line, RPMI-8226, implanted in SCID mice.
  • Hu38SB19 was formulated in phosphate buffer saline without Ca 2+ and Mg 2+ , pH7.4. Hu38SB19 was administered intravenously on days 16, 19, 22, 25 after tumor implantation.
  • Melphalan was formulated in 5 % ethanol, 5 % polysorbate 80, 90 % sodium chloride 0.9 % in water. Melphalan was administered intravenously simultaneously to hu38SB19 on days 16, 19, 22, 25 after tumor implantation (except for the highest dose of the combination for which treatment was stopped on day 19 when toxicity was reached).
  • Toxicity was declared at dosages inducing ⁇ 20 % body weight loss or ⁇ 10 % drug death
  • Tumor Free Survivors correspond to complete regression below the limit of palpation (63 mg) for the entire duration of the study (>100 days post last treatment).
  • Therapeutic Synergism a combination has therapeutic synergism if it is more active than the best single agent of the study (by at least 1 log cell kill).
  • Toxicity for melphalan alone was observed at a dose of 16.1 mg/kg/injection, with 3 drug-related deaths out of 5 mice, i.e. above the 10 % threshold.
  • the 10 mg/kg/inj dose was found to be active with a log cell kill of 1.9.
  • hu38SB19 the product was well tolerated at a dose of 40 mg/kg/inj. No toxicity was observed, which can be explained by the lack of cross-reactivity of the antibody with murine CD38. The log cell kill was 0.5, indicating that hu38DB19 was not active under these conditions.
  • the combination of melphalan at 16.1 mg/kg/inj and hu38SB19 at 40 mg/kg/inj was toxic, with 5 out of 5 drug-related deaths, i.e. very similar to what was observed with melphalan alone at the same dose.
  • the dose of 10 mg/kg/inj of melphalan with 40 mg/kg/inj of hu38SB19 was considered to be the HNTD.
  • the log cell kill was 2.2, indicating that the combination was as active as the best agent, i.e. melphalan.
  • LP1 a human multiple myeloma model highly sensitive to melphalan in comparison to RPMI-8226.
  • the model was implanted on SCID mice.
  • Hu38SB19 was formulated in glucose 5 % in water. Hu38SB19 was administered intravenously on days 12, 15, 18, 21 after tumor implantation.
  • Melphalan was formulated in 5 % ethanol, 5 % polysorbate 80, 90 % sodium chloride 0.9 % in water. Melphalan was administered intravenously simultaneously to hu38SB19 on days 12, 15, 18, 21 after tumor implantation.
  • Toxicity was declared at dosages inducing ⁇ 20 % body weight loss or ⁇ 10 % drug death
  • Toxicity for melphalan alone was observed at a dose of 16.1 mg/kg/injection, with 33.6 % body weight loss at nadir on day 22, i.e. above the 20 % threshold and 4/5 drug-related deaths.
  • hu38SB19 the product was well tolerated at a dose of 40 mg/kg/inj. No toxicity was observed, which can be explained by the lack of cross-reactivity of the antibody with murine CD38. The log cell kill was 0.2, indicating that hu38DB19 was not active under these conditions.
  • the combination of melphalan at 16.1 mg/kg/inj and hu38SB19 at 40 mg/kg/inj was toxic, with 34.2 % body weight loss at nadir on day 22 and 5/5 drug-related deaths, i.e. very similar to what was observed with melphalan alone at the same dose.
  • the dose of 10 mg/kg/inj of melphalan with 40 mg/kg/inj of hu38SB19 was considered to be the highest nontoxic dose. Remarkably, this dose displayed a high antitumor efficacy of 18.9 log cell kill (and 1/5 TFS on day 148) and demonstrated therapeutic synergism in comparison to the HNTD of the melphalan alone (9.3 log cell kill).
  • BWC body weight change
  • T-C tumor growth delay
  • HNTD highest nontoxic dose
  • HDT highest dose tested
  • IV intravenous.
  • Table II Combination of hu38SB19 and melphalan against advanced human multiple myeloma LP1 implanted in SCID female mice.
  • Formulation: hu38SB19 glucose 5 % in water, melphalan: 5 % ethanol, 5 % polysorbate 80, 90 % sodium chloride 0.9 % in water.
  • BWC body weight change
  • T-C tumor growth delay
  • HNTD highest nontoxic dose
  • HDT highest dose tested
  • TFS tumor free survivors
  • NTBA Non tumor bearing animals
  • IV intravenous. 8 treatments were stopped on day 18 when toxicity was reached.

Landscapes

  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Mycology (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Pharmaceutical composition comprising an antibody specifically recognizing CD38 and melphalan.

Description

Antitumor combinations containing antibodies recognizing specifically CD38 and melphalan.
The present invention relates to combinations of monoclonal antibodies directed against CD38 and melphalan which are therapeutically useful in the treatment of neoplastic diseases.
CD38 is a 45 kD type Il transmembrane glycoprotein with a long C-terminal extracellular domain and a short N-terminal cytoplasmic domain. The CD38 protein is a bifunctional ectoenzyme that can catalyze the conversion of NAD+ into cyclic ADP- ribose (cADPR) and also hydrolyze cADPR into ADP-ribose. CD38 is upregulated and has been implicated in many hematopoietic malignancies.
Monoclonal antibodies 38SB13, 38SB18, 38SB19, 38SB30, 38SB31 , and 38SB39, which specifically recognize CD38, are described in PCT application WO2008/047242. Said anti-CD38 antibodies are capable of killing CD38+ cells by three different cytotoxic mechanisms, induction of apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). In addition, these antibodies are able to directly induce apoptosis of CD38+ cells, even without the presence of stroma cells or stroma-derived cytokines. Melphalan is an alkylating agent used in chemotherapy. Nevertheless, there is still a need for new and efficacious medicaments for treating cancer.
It has now been found, and for this invention, that the efficacy of the humanized anti- CD38 antibodies may be considerably improved when it is administered in combination with at least one substance which is therapeutically useful in anticancer treatments and has a mechanism identical to or different from the one of the humanized anti-CD38 antibodies and which is limited in the present invention to melphalan.
The term "antibody" is used herein in the broadest sense and specifically covers monoclonal antibodies (including full length monoclonal antibodies) of any isotype such as IgG, IgM, IgA, IgD and IgE, polyclonal antibodies, multispecific antibodies, chimeric antibodies, and antibody fragments. A typical IgG antibody is comprised of two identical heavy chains and two identical light chains that are joined by disulfide bonds. Each heavy and light chain contains a constant region and a variable region. Each variable region contains three segments called "complementarity-determining regions" ("CDRs") or "hypervariable regions", which are primarily responsible for binding an epitope of an antigen. They are usually referred to as CDR1 , CDR2, and CDR3, numbered sequentially from the N-terminus. The more highly conserved portions of the variable regions outside of the CDRs are called the "framework regions".
As used herein, "VH" or "VH" refers to the variable region of an immunoglobulin heavy chain of an antibody, including the heavy chain of an Fv, scFv, dsFv, Fab, Fab' or F(ab')2 fragment. Reference to "VL" or "VL" refers to the variable region of the immunoglobulin light chain of an antibody, including the light chain of an Fv, scFv, dsFv, Fab, Fab' or F(ab')2 fragment.
The 38SB13 antibody comprises at least one heavy chain having an amino acid sequence consisting of SEQ ID NO: 50 and at least one light chain having an amino acid sequence consisting of SEQ ID NO: 38, said heavy chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 1 , 2, and 3, and said light chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 4, 5, and 6.
The 38SB18 antibody comprises at least one heavy chain having an amino acid sequence consisting of SEQ ID NO: 52 and at least one light chain having an amino acid sequence consisting of SEQ ID NO: 40, said heavy chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 7, 8, and 9, and said light chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 10, 11 , and 12.
The 38SB19 antibody comprises at least one heavy chain having an amino acid sequence consisting of SEQ ID NO: 54 and at least one light chain having an amino acid sequence consisting of SEQ ID NO: 42, said heavy chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 13, 14, and 15, and said light chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 16, 17, and 18.
The 38SB30 antibody comprises at least one heavy chain having an amino acid sequence consisting of SEQ ID NO: 56 and at least one light chain having an amino acid sequence consisting of SEQ ID NO: 44, said heavy chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 19, 20, and 21 , and said light chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 22, 23, and 24.
The 38SB31 antibody comprises at least one heavy chain having an amino acid sequence consisting of SEQ ID NO: 58 and at least one light chain having an amino acid sequence consisting of SEQ ID NO: 46, said heavy chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 25, 26, and 27, and said light chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 28, 29, and 30.
The 38SB39 antibody comprises at least one heavy chain having an amino acid sequence consisting of SEQ ID NO: 60 and at least one light chain having an amino acid sequence consisting of SEQ ID NO: 48, said heavy chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 31 , 32, and 33, and said light chain comprising three sequential CDRs having amino acid sequences consisting of SEQ ID NOS: 34, 35, and 36.
The hybridoma cell lines producing the 38SB13, 38SB18, 38SB19, 38SB30, 38SB31 , and 38SB39 murine anti-CD38 antibodies have been deposited at the American Type Culture Collection (10801 University Bid, Manassas, VA, 201 10-2209, USA), on June 21 , 2006, under the deposit numbers PTA-7667, PTA-7669, PTA-7670, PTA-7666, PTA-7668, and PTA-7671 , respectively (as described in WO2008/047242).
The term "humanized antibody", as used herein, refers to a chimeric antibody which contain minimal sequence derived from non-human immunoglobulin. The goal of humanization is a reduction in the immunogenicity of a xenogenic antibody, such as a murine antibody, for introduction into a human, while maintaining the full antigen binding affinity and specificity of the antibody. Humanized antibodies, or antibodies adapted for non-rejection by other mammals, may be produced using several technologies such as resurfacing and CDR grafting. As used herein, the resurfacing technology uses a combination of molecular modelling, statistical analysis and mutagenesis to alter the non-CDR surfaces of antibody variable regions to resemble the surfaces of known antibodies of the target host. The CDR grafting technology involves substituting the complementarity determining regions of, for example, a mouse antibody, into a human framework domain, e.g., see WO 92/22653. Humanized chimeric antibodies preferably have constant regions and variable regions other than the complementarity determining regions (CDRs) derived substantially or exclusively from the corresponding human antibody regions and CDRs derived substantially or exclusively from a mammal other than a human.
Strategies and methods for the resurfacing of antibodies, and other methods for reducing immunogenicity of antibodies within a different host, are disclosed in US Patent 5,639,641 , which is hereby incorporated in its entirety by reference. Antibodies can be humanized using a variety of other techniques including CDR-grafting (EP 0 239 400; WO 91/09967; U.S. Pat. Nos. 5,530,101 ; and 5,585,089), veneering or resurfacing (EP 0 592 106; EP 0 519 596; Padlan E. A., 1991 , Molecular Immunology 28(4/5): 489-498; Studnicka G. M. et al., 1994, Protein Engineering, 7(6): 805-814; Roguska M.A. et al., 1994, PNAS, 91 : 969-973), chain shuffling (U.S. Pat. No. 5,565,332), and identification of flexible residues (PCT/US2008/074381 ). Human antibodies can be made by a variety of methods known in the art including phage display methods. See also U.S. Pat. Nos. 4,444,887, 4,716,111 , 5,545,806, and
5,814,318; and international patent application publication numbers WO 98/46645, WO 98/50433, WO 98/24893, WO 98/16654, WO 96/34096, WO 96/33735, and WO 91/10741 (said references incorporated by reference in their entireties).
The anti-CD38 antibodies of the pharmaceutical combination of the present invention are humanized antibodies which recognize CD38 and kill CD38+ cells by apoptosis, ADCC, and CDC. In a further embodiment, the humanized antibodies of the invention are capable of killing said CD38+ cells by apoptosis even in the absence of stroma cells or stroma-derived cytokines.
A preferred embodiment of such a humanized antibody is a humanized 38SB13, 38SB18, 38SB19, 38SB30, 38SB31 , or 38SB39 antibody, or an epitope-binding fragment thereof.
The CDRs of the 38SB13, 38SB18, 38SB19, 38SB30, 38SB31 , and 38SB39 antibodies are identified by modelling and their molecular structures have been predicted. Thus, in one embodiment, this invention provides humanized antibodies or epitope-binding fragment thereof comprising one or more CDRs having an amino acid sequence selected from the group consisting of SEQ ID NOS: 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, and 36. In a preferred embodiment, a humanized version of 38SB13 is provided, which comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 1 , 2, and 3, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 4, 5, and 6. In another preferred embodiment, a humanized version of 38SB18 is provided, which comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 7, 8, and 9, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 10, 11 , and 12. In another preferred embodiment, a humanized version of 38SB19 is provided, which comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity- determining regions having amino acid sequences represented by SEQ ID NOS: 13, 14, and 15, and wherein said light chain comprises three sequential complementarity- determining regions having amino acid sequences represented by SEQ ID NOS: 16, 17, and 18. In another preferred embodiment, a humanized version of 38SB30 is provided, which comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 19, 20, and 21 , and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 22, 23, and 24. In another preferred embodiment, a humanized version of 38SB31 is provided, which comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 25, 26, and 27, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 28, 29, and 30. In another preferred embodiment, a humanized version of 38SB39 is provided, which comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 31 , 32, and 33, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 34, 35, and 36. In one embodiment, this invention provides humanized antibodies or fragments thereof which comprise a VH having an amino acid sequence selected from the group of SEQ ID NOS: 66 and 72. In a preferred embodiment, a humanized 38SB19 antibody is provided which comprises a VH having an amino acid sequence represented by SEQ ID NO: 66. In another preferred embodiment, a humanized 38SB31 antibody is provided which comprises a VH having an amino acid sequence represented by SEQ ID NO: 72.
In another embodiment, this invention provides humanized antibodies or fragments thereof which comprise a VL having an amino acid sequence selected from the group of SEQ ID NOS: 62, 64, 68, and 70. In a preferred embodiment, a humanized 38SB19 antibody is provided which comprises a VL having an amino acid sequence chosen from the group of SEQ ID NOS: 62 and 64. In another preferred embodiment, a humanized 38SB31 antibody is provided which comprises a VL having an amino acid sequence chosen from the group of SEQ ID NOS: 68 and 70.
Each of the humanized versions of the 38SB13, 38SB18, 38SB19, 38SB30, 38SB31 , and 38SB39 antibodies has been shown to be particularly advantageous as an anticancer agent. The preparation, physical properties and beneficial pharmacological properties thereof are described in WO 2008/047242, which is incorporated by reference herein in its entirety. Generally, the doses used for treating human beings, which depend on factors distinctive to the subject to be treated, are between 1 and 150 mg/kg administered orally or between 1 and 150 mg/kg administered intravenously.
Melphalan (brand name, Alkeran™), is a chemotherapy drug belonging to the class of nitrogen mustard alkylating agents. Otherwise known as L-Phenylalanine Mustard, or L-PAM, melphalan is a phenylalanine derivative of mechlorethamine and is a bifunctional alkylating agent. Formation of carbonium intermediates from each of the two bis-2-chloroethyl groups enables alkylation through covalent binding with the 7- nitrogen of guanine on DNA, cross-linking two DNA strands and thereby preventing cell replication. Melphalan is used primarily to treat multiple myeloma and ovarian cancer, and occasionally malignant melanoma. It is usually administered orally or intravenously.
One aspect of the invention is a pharmaceutical composition comprising an anti-CD38 antibody in combination with at least melphalan. Since the activity of the products depends on the doses used, it is thus possible to use lower doses and to increase the activity while decreasing the toxicity phenomena. The improved efficacy of a combination according to the invention may be demonstrated by determination of the therapeutic synergy. A combination manifests therapeutic synergy if it is therapeutically superior to the best agent of the study used alone at its maximum tolerated dose or at its highest dose tested when toxicity cannot be reached in the animal species.
This efficacy may be quantified, for example, by the log™ cells kill, which is determined according to the following formula:
log™ cell kill = T-C (days)/3.32* Td
in which T - C represents the tumor growth delay, which is the median time in days for the tumors of the treated group (T) and the tumors of the control group (C) to reach a predetermined value (1 g for example), and Td represents the time in days needed for the volume of the tumor to double in the control animals [T. H. Corbett et al., Cancer, 40: 2660-2680 (1977); F. M. Schabel et al., Cancer Drug Development, Part B, Methods in Cancer Research, 17: 3-51 , New York, Academic Press Inc. (1979)]. A product is considered to be active if log™ cell kill is greater than or equal to 0.7. A product is considered to be very active if log™ cell kill is greater than 2.8.
The combination will manifest therapeutic synergy when the log™ cell kill is greater than the value of the log™ cell kill of the best constituent when it is administered alone and used at its maximum tolerated dose or at its highest dose tested.
The efficacy of the combinations on solid tumors may be determined experimentally in the following manner:
The animals subjected to the experiment, generally mice, are subcutaneously grafted bilaterally with 30 to 60 mg of a tumor fragment on day 0. The animals bearing tumors are randomized based on their tumor size before being subjected to the various treatments and controls. Chemotherapy begins when tumors have reached a predetermined size after grafting, depending on the type of tumor, and the animals are observed every day. The different animal groups are weighed daily during treatment until the maximum weight loss is reached and subsequent full weight recovery has occurred. The groups are then weighed once or twice a week until the end of the trial. The tumors are measured 1 to 5 times a week, depending on the tumor doubling time, until the tumor reaches approximately 2 g, or until the animal dies (if this occurs before the tumor reaches 2 g). The animals are necropsied immediately after euthanasia or death.
The antitumor activity is determined in accordance with the different parameters recorded.
Results obtained with combinations of hu38SB19 and melphalan used at their optimal doses are indicated hereunder as examples.
The present invention also relates, therefore, to pharmaceutical compositions containing the combinations according to the invention.
The constituents of which the combination are composed may be administered simultaneously, semi-simultaneously, separately, or spaced out over a period of time so as to obtain the maximum efficacy of the combination; it being possible for each administration to vary in its duration from a rapid administration to a continuous perfusion.
As a result, for the purposes of the present invention, the combinations are not exclusively limited to those which are obtained by physical association of the constituents, but also to those which permit a separate administration, which can be simultaneous or spaced out over a period of time.
The compositions according to the invention are preferably compositions which can be administered parentally. However, these compositions may be administered orally, subcutaneously or intraperitoneal^ in the case of localized regional therapies.
The compositions for parental administration are generally pharmaceutically acceptable, sterile solutions or suspensions which may optionally be prepared as required at the time of use. For the preparation of non-aqueous solutions or suspensions, natural vegetable oils such as olive oil, sesame oil or liquid petroleum or injectable organic esters such as ethyl oleate may be used. The sterile aqueous solutions can consist of a solution of the product in water. The aqueous solutions are suitable for intravenous administration provided the pH is appropriately adjusted and the solution is made isotonic, for example with a sufficient amount of sodium chloride or glucose. The sterilization may be carried out by heating or by any other means which does not adversely affect the composition. The combinations may also take the form of liposomes or the form of an association with carriers as cyclodextrins or polyethylene glycols.
The compositions for oral, subcutaneous or intraperitoneal administration are preferably aqueous suspensions or solutions.
In the combinations according to the invention, the application of the constituents of which may be simultaneous, separate or spaced out over a period of time, it is especially advantageous for the amount of humanized anti-CD38 antibody to represent from 10 to 90 % by weight of the combination, it being possible for this content to vary in accordance with the nature of the associated substance, the efficacy sought and the nature of the cancer to be treated.
The combinations according to the invention are especially useful in the treatment of several types of cancers including (but not limited to) the following: carcinomas and adenocarcinomas, including that of the bladder, breast, colon, head-and-neck, prostate, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin, and including squamous cell carcinoma ; hematopoietic tumors of lymphoid lineage, including multiple myeloma, leukemia, acute and chronic lymphocytic (or lymphoid) leukemia, acute and chronic lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, non- Hodgkin lymphoma (e.g. Burkitt's lymphoma) ; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous (myeloid or myelocytic) leukemias, and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma, osteosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannomas; and other tumors, including melanoma, teratocarcinoma, xeroderma pigmentosum, keratoacanthoma, and seminoma, and other cancers yet to be determined in which CD38 is expressed. They are mainly useful for treating leukemia, lymphoma and cancers resistant to the commonly used anticancer agents as the anti-CD38 antibodies of the invention have a unique mechanism of action.
Thus, the invention also encompasses the use of the above combinations for the manufacture of a medicament for the treatment of cancer. Example:
In this example, the effectiveness of an anti-CD38 antibody/melphalan combination of the invention for tumor growth inhibition was demonstrated in vivo.
The first selected tumor model was a transplantable human multiple myeloma cell line, RPMI-8226, implanted in SCID mice.
Hu38SB19 was formulated in phosphate buffer saline without Ca 2+ and Mg2+, pH7.4. Hu38SB19 was administered intravenously on days 16, 19, 22, 25 after tumor implantation.
Melphalan was formulated in 5 % ethanol, 5 % polysorbate 80, 90 % sodium chloride 0.9 % in water. Melphalan was administered intravenously simultaneously to hu38SB19 on days 16, 19, 22, 25 after tumor implantation (except for the highest dose of the combination for which treatment was stopped on day 19 when toxicity was reached).
The results of the experiment are reported in Table 1.
Tumor doubling time = 3.2 days.
The following end points have been used: • Toxicity was declared at dosages inducing ≥ 20 % body weight loss or ≥ 10 % drug death,
• Antitumor efficacy was determined by calculating Iog10 cell kill = (T-C) / [3.32 x (tumor doubling time in days)]
(T meaning the median time of the treated mice to reach 1000 mg and C the median time (25.3 days) of the control mice to reach the same size; tumor-free survivors are excluded from these calculations and are tabulated separately). No antitumor activity was declared for log cell kill < 0.7, and the treatment was declared highly active for log cell kill ≥ 2.8
• Tumor Free Survivors (TFS): correspond to complete regression below the limit of palpation (63 mg) for the entire duration of the study (>100 days post last treatment). • Therapeutic Synergism: a combination has therapeutic synergism if it is more active than the best single agent of the study (by at least 1 log cell kill).
Toxicity for melphalan alone was observed at a dose of 16.1 mg/kg/injection, with 3 drug-related deaths out of 5 mice, i.e. above the 10 % threshold. The highest nontoxic dose (HNTD) for melphalan was 10 mg/kg/inj (total injected dose = 40 mg/kg). The 10 mg/kg/inj dose was found to be active with a log cell kill of 1.9.
Regarding hu38SB19, the product was well tolerated at a dose of 40 mg/kg/inj. No toxicity was observed, which can be explained by the lack of cross-reactivity of the antibody with murine CD38. The log cell kill was 0.5, indicating that hu38DB19 was not active under these conditions.
The combination of melphalan at 16.1 mg/kg/inj and hu38SB19 at 40 mg/kg/inj was toxic, with 5 out of 5 drug-related deaths, i.e. very similar to what was observed with melphalan alone at the same dose. The dose of 10 mg/kg/inj of melphalan with 40 mg/kg/inj of hu38SB19 was considered to be the HNTD. At this dose, the log cell kill was 2.2, indicating that the combination was as active as the best agent, i.e. melphalan.
Another experiment was performed with LP1 , a human multiple myeloma model highly sensitive to melphalan in comparison to RPMI-8226. The model was implanted on SCID mice.
Hu38SB19 was formulated in glucose 5 % in water. Hu38SB19 was administered intravenously on days 12, 15, 18, 21 after tumor implantation.
Melphalan was formulated in 5 % ethanol, 5 % polysorbate 80, 90 % sodium chloride 0.9 % in water. Melphalan was administered intravenously simultaneously to hu38SB19 on days 12, 15, 18, 21 after tumor implantation.
The results of the experiment are reported in Table 2.
Tumor doubling time = 1.5 days.
The following end points have been used: • Toxicity was declared at dosages inducing ≥ 20 % body weight loss or ≥ 10 % drug death,
• Antitumor efficacy was determined by calculation of the Iog10 cell kill = (T-C) / [3.32 x (tumor doubling time in days)] (T meaning the median time of the treated mice to reach 1000 mg and C the median time (16.8 days) of the control mice to reach the same size; tumor-free survivors are excluded from these calculations and are tabulated separately). No antitumor activity was declared for log cell kill < 0.7, and the treatment was declared highly active for log cell kill ≥ 2.8 • Therapeutic Synergism: A combination has therapeutic synergism if it is more active than the best single agent of the study (by at least 1 log cell kill).
Toxicity for melphalan alone was observed at a dose of 16.1 mg/kg/injection, with 33.6 % body weight loss at nadir on day 22, i.e. above the 20 % threshold and 4/5 drug-related deaths. The HNTD for melphalan was 10 mg/kg/inj (total injected dose = 40 mg/kg). The 10 mg/kg/inj dose was found to be highly active with a 9.3 log cell kill.
Regarding hu38SB19, the product was well tolerated at a dose of 40 mg/kg/inj. No toxicity was observed, which can be explained by the lack of cross-reactivity of the antibody with murine CD38. The log cell kill was 0.2, indicating that hu38DB19 was not active under these conditions.
The combination of melphalan at 16.1 mg/kg/inj and hu38SB19 at 40 mg/kg/inj was toxic, with 34.2 % body weight loss at nadir on day 22 and 5/5 drug-related deaths, i.e. very similar to what was observed with melphalan alone at the same dose. The dose of 10 mg/kg/inj of melphalan with 40 mg/kg/inj of hu38SB19 was considered to be the highest nontoxic dose. Remarkably, this dose displayed a high antitumor efficacy of 18.9 log cell kill (and 1/5 TFS on day 148) and demonstrated therapeutic synergism in comparison to the HNTD of the melphalan alone (9.3 log cell kill). Therapeutic synergism was maintained at lower dose levels of the combination in comparison to equitoxic doses of melphalan alone. Table I: Combination of hu38SB19 and melphalan against advanced human multiple myeloma RPMI-8226 implanted in SCID female mice.
CO
Figure imgf000014_0001
Tumor doubling time = 3.2 days. Median tumor size at start of therapy = 131-148 mg. Time for median tumor to reach 1000 mg = 25.3 days. Formulation: hu38SB19 = phosphate buffer saline without Ca2+ and Mg2+, pH 7.4; melphalan = 5 % ethanol, 5 % polysorbate 80, 90 % sodium chloride 0.9 % in water. BWC = body weight change, T-C = tumor growth delay, HNTD = highest nontoxic dose, HDT = highest dose tested, IV = intravenous.
Table II: Combination of hu38SB19 and melphalan against advanced human multiple myeloma LP1 implanted in SCID female mice.
Figure imgf000015_0001
Tumor doubling time = 1.5 days. Median tumor size at start of therapy = 11 1-127 mg. Time for median tumor to reach 1000 mg = 16.8 days. Formulation: hu38SB19= glucose 5 % in water, melphalan: 5 % ethanol, 5 % polysorbate 80, 90 % sodium chloride 0.9 % in water. BWC = body weight change, T-C= tumor growth delay, HNTD = highest nontoxic dose, HDT = highest dose tested, TFS = tumor free survivors, NTBA = Non tumor bearing animals, IV= intravenous.8 treatments were stopped on day 18 when toxicity was reached.

Claims

Claims
1. A pharmaceutical combination comprising an antibody specifically recognizing CD38 and at least melphalan, wherein said antibody is capable of killing a CD38+ cell by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC).
2. The combination of claim 1 , wherein said antibody is a humanized antibody.
3. The combination of claim 2 wherein said antibody comprises one or more complementarity-determining region having an amino acid sequence selected from the group consisting of SEQ ID NOS: 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, and 36.
4. The combination of claim 3 wherein said antibody comprises at least one heavy chain and at least one light chain, wherein said heavy chain has an amino acid sequence represented by SEQ ID NO: 66 and said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 13, 14, and 15, and wherein said light chain has an amino acid sequence selected from the group of SEQ ID NOS: 62 and 64, and said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 16, 17, and 18.
5. The combination of claim 3 wherein said antibody comprises at least one heavy chain and at least one light chain, wherein said heavy chain has an amino acid sequence represented by SEQ ID NO: 72 and said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 25, 26, and 27, and wherein said light chain has an amino acid sequence selected from the group of SEQ ID NOS: 68 and 70, and said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 28, 29, and 30.
6. Use of an antibody specifically recognizing CD38 for the preparation of a pharmaceutical combination according to claim 1 for the manufacture of a medicament for the treatment of cancer.
7. The use of claim 6, wherein said antibody is a humanized antibody.
8. The use of claim 7 wherein said antibody comprises one or more complementarity-determining region having an amino acid sequence selected from the group consisting of SEQ ID NOS: 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, and 36.
9. The use of claim 8 wherein said antibody comprises at least one heavy chain and at least one light chain, wherein said heavy chain has an amino acid sequence represented by SEQ ID NO: 66 and said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 13, 14, and 15, and wherein said light chain has an amino acid sequence selected from the group of SEQ ID NOS: 62 and 64, and said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 16, 17, and 18.
10. The use of claim 8 wherein said antibody comprises at least one heavy chain and at least one light chain, wherein said heavy chain has an amino acid sequence represented by SEQ ID NO: 72 and said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 25, 26, and 27, and wherein said light chain has an amino acid sequence selected from the group of SEQ ID NOS: 68 and 70, and said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 28, 29, and 30.
PCT/IB2009/055389 2008-11-28 2009-11-27 Antitumor combinations containing antibodies recognizing specifically cd38 and melphalan WO2010061357A1 (en)

Priority Applications (19)

Application Number Priority Date Filing Date Title
JP2011538092A JP2012510461A (en) 2008-11-28 2009-11-27 Antitumor combination containing antibody specifically recognizing CD38 and melphalan
EA201100864A EA026867B1 (en) 2008-11-28 2009-11-27 Antitumor combinations containing melphalan and antibodies specifically recognizing cd38
NZ593027A NZ593027A (en) 2008-11-28 2009-11-27 Antitumor combinations containing antibodies recognizing specifically cd38 and melphalan
US13/130,862 US9259406B2 (en) 2008-11-28 2009-11-27 Antitumor combinations containing antibodies recognizing specifically CD38 and melphalan
EP09775302A EP2370094A1 (en) 2008-11-28 2009-11-27 Antitumor combinations containing antibodies recognizing specifically cd38 and melphalan
CN200980148094.4A CN102264385B (en) 2008-11-28 2009-11-27 Antitumor combinations containing antibodies recognizing specifically cd38 and melphalan
UAA201108006A UA107069C2 (en) 2008-11-28 2009-11-27 Anticancer combinations containing melphalan and antibody that specifically recognizes the cd38
CA2744990A CA2744990C (en) 2008-11-28 2009-11-27 Antitumor combinations containing antibodies recognizing specifically cd38 and melphalan
MEP-2011-93A ME01136B (en) 2008-11-28 2009-11-27 Antitumor combinations containing antibodies recognizing specifically cd38 and melphalan
KR1020117014746A KR101733252B1 (en) 2008-11-28 2009-11-27 Antitumor combinations containing antibodies recognizing specifically cd38 and melphalan
MX2011005670A MX342625B (en) 2008-11-28 2009-11-27 Antitumor combinations containing antibodies recognizing specifically cd38 and melphalan.
AU2009321249A AU2009321249B2 (en) 2008-11-28 2009-11-27 Antitumor combinations containing antibodies recognizing specifically CD38 and melphalan
SG2011037967A SG171820A1 (en) 2008-11-28 2009-11-27 Antitumor combinations containing antibodies recognizing specifically cd38 and melphalan
BRPI0921864-5A BRPI0921864B1 (en) 2008-11-28 2009-11-27 ANTITUMOR COMBINATIONS CONTAINING ANTIBODIES THAT SPECIFICALLY RECOGNIZE CD38 AND MELPHALAN AND USES OF THE ANTIBODY THAT SPECIFICALLY RECOGNIZE CD38
TN2011000232A TN2011000232A1 (en) 2008-11-28 2011-05-11 Antitumor combinations containing antibodies recognizing specifically cd38 melphalan
IL213116A IL213116B (en) 2008-11-28 2011-05-24 Antitumor combinations containing antibodies recognizing specifically cd38 and melphalan
ZA2011/03925A ZA201103925B (en) 2008-11-28 2011-05-27 Antitumor combinations containing antibodies recognizing specifically cd38 and melphalan
MA33937A MA32896B1 (en) 2008-11-28 2011-06-13 ANTICANCER COMBINATIONS CONTAINING SPECIFICALLY RECOGNIZING CD38 AND MELPHALAN ANTIBODIES
HK12105154.7A HK1164165A1 (en) 2008-11-28 2012-05-25 Antitumor combinations containing antibodies recognizing specifically cd38 and melphalan cd38

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP08291116A EP2191840A1 (en) 2008-11-28 2008-11-28 Antitumor combinations containing antibodies recognizing specifically CD38 and melphalan
EP08291116.5 2008-11-28

Publications (1)

Publication Number Publication Date
WO2010061357A1 true WO2010061357A1 (en) 2010-06-03

Family

ID=40578382

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2009/055389 WO2010061357A1 (en) 2008-11-28 2009-11-27 Antitumor combinations containing antibodies recognizing specifically cd38 and melphalan

Country Status (33)

Country Link
US (1) US9259406B2 (en)
EP (2) EP2191840A1 (en)
JP (3) JP2012510461A (en)
KR (1) KR101733252B1 (en)
CN (1) CN102264385B (en)
AR (1) AR074219A1 (en)
AU (1) AU2009321249B2 (en)
BR (1) BRPI0921864B1 (en)
CA (1) CA2744990C (en)
CL (1) CL2011001254A1 (en)
CO (1) CO6440557A2 (en)
CR (1) CR20110280A (en)
EA (1) EA026867B1 (en)
EC (1) ECSP11011062A (en)
HK (1) HK1164165A1 (en)
HN (1) HN2011001417A (en)
IL (1) IL213116B (en)
MA (1) MA32896B1 (en)
ME (1) ME01136B (en)
MX (1) MX342625B (en)
MY (1) MY164577A (en)
NI (1) NI201100105A (en)
NZ (1) NZ593027A (en)
PA (1) PA8850101A1 (en)
PE (1) PE20120340A1 (en)
SG (1) SG171820A1 (en)
SV (1) SV2011003924A (en)
TN (1) TN2011000232A1 (en)
TW (1) TWI454260B (en)
UA (1) UA107069C2 (en)
UY (1) UY32263A (en)
WO (1) WO2010061357A1 (en)
ZA (1) ZA201103925B (en)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012041800A1 (en) 2010-09-27 2012-04-05 Morphosys Ag Anti-cd38 antibody and lenalidomide or bortezomib for the treatment of multiple myeloma and nhl
WO2012076663A1 (en) * 2010-12-10 2012-06-14 Sanofi Antitumor combinations containing antibodies recognizing specifically cd38 and bortezomib
WO2014048921A1 (en) 2012-09-25 2014-04-03 Morphosys Ag Combinations and uses thereof
WO2015066450A1 (en) 2013-10-31 2015-05-07 Sanofi Specific anti-cd38 antibodies for treating human cancers
US10385135B2 (en) 2015-11-03 2019-08-20 Janssen Biotech, Inc. Subcutaneous formulations of anti-CD38 antibodies and their uses
US10494444B2 (en) 2010-12-30 2019-12-03 Takeda Pharmaceutical Company Limited Anti-CD38 antibodies
US10556961B2 (en) 2014-02-28 2020-02-11 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of acute lymphoblastic leukemia
US10604580B2 (en) 2014-09-09 2020-03-31 Janssen Biotech, Inc. Combination therapies with anti-CD38 antibodies
US10617757B2 (en) 2014-08-08 2020-04-14 The Regents Of The University Of California Methods for treating multiple myeloma
US10668149B2 (en) 2015-06-22 2020-06-02 Janssen Biotech, Inc. Combination therapies for heme malignancies with anti-CD38 antibodies and survivin inhibitors
US10766965B2 (en) 2015-05-20 2020-09-08 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of light chain amyloidosis and other CD38-positive hematological malignancies
US10781261B2 (en) 2015-11-03 2020-09-22 Janssen Biotech, Inc. Subcutaneous formulations of anti-CD38 antibodies and their uses
WO2020187718A1 (en) 2019-03-15 2020-09-24 Morphosys Ag Anti-cd38 antibodies and pharmaceutical compositions thereof for the treatment of autoantibody-mediated autoimmune disease
US10793630B2 (en) 2014-12-04 2020-10-06 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of acute myeloid leukemia
US10800851B2 (en) 2014-02-28 2020-10-13 Janssen Biotech, Inc. Combination therapies with anti-CD38 antibodies
US11021543B2 (en) 2015-06-24 2021-06-01 Janssen Biotech, Inc. Immune modulation and treatment of solid tumors with antibodies that specifically bind CD38
WO2021113739A1 (en) 2019-12-05 2021-06-10 Thomas Ballet Formulations of anti-cd38 antibodies for subcutaneous administration
WO2022152823A1 (en) 2021-01-14 2022-07-21 Morphosys Ag Anti-cd38 antibodies and their uses
WO2022184676A1 (en) 2021-03-01 2022-09-09 Morphosys Ag Anti-cd38 antibodies for use in the treatment of antibody-mediated transplant rejection
WO2023001804A1 (en) 2021-07-19 2023-01-26 Morphosys Ag Treatment of anti-pla2r autoantibody-mediated membranous nephropathy
US11618787B2 (en) 2017-10-31 2023-04-04 Janssen Biotech, Inc. Methods of treating high risk multiple myeloma
US11655302B2 (en) 2019-06-10 2023-05-23 Sanofi Anti-CD38 antibodies and formulations

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2191840A1 (en) 2008-11-28 2010-06-02 Sanofi-Aventis Antitumor combinations containing antibodies recognizing specifically CD38 and melphalan
CA2796464C (en) 2010-04-16 2021-08-03 Immune Disease Institute, Inc. Sustained polypeptide expression from synthetic, modified rnas and uses thereof
EP2600901B1 (en) 2010-08-06 2019-03-27 ModernaTX, Inc. A pharmaceutical formulation comprising engineered nucleic acids and medical use thereof
HRP20220796T1 (en) 2010-10-01 2022-10-14 ModernaTX, Inc. Ribonucleic acids containing n1-methyl-pseudouracils and uses thereof
CA2831613A1 (en) 2011-03-31 2012-10-04 Moderna Therapeutics, Inc. Delivery and formulation of engineered nucleic acids
US9464124B2 (en) 2011-09-12 2016-10-11 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
EP3492109B1 (en) 2011-10-03 2020-03-04 ModernaTX, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
RS63244B1 (en) 2011-12-16 2022-06-30 Modernatx Inc Modified mrna compositions
US9572897B2 (en) 2012-04-02 2017-02-21 Modernatx, Inc. Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
WO2013151664A1 (en) 2012-04-02 2013-10-10 modeRNA Therapeutics Modified polynucleotides for the production of proteins
US9283287B2 (en) 2012-04-02 2016-03-15 Moderna Therapeutics, Inc. Modified polynucleotides for the production of nuclear proteins
US9303079B2 (en) 2012-04-02 2016-04-05 Moderna Therapeutics, Inc. Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
PL2922554T3 (en) 2012-11-26 2022-06-20 Modernatx, Inc. Terminally modified rna
US10342869B2 (en) 2012-12-07 2019-07-09 The Regents Of The University Of California Compositions comprising anti-CD38 antibodies and lenalidomide
UA118255C2 (en) * 2012-12-07 2018-12-26 Санофі Compositions comprising anti-cd38 antibodies and lenalidomide
US8980864B2 (en) 2013-03-15 2015-03-17 Moderna Therapeutics, Inc. Compositions and methods of altering cholesterol levels
EP3052106A4 (en) 2013-09-30 2017-07-19 ModernaTX, Inc. Polynucleotides encoding immune modulating polypeptides
SG11201602503TA (en) 2013-10-03 2016-04-28 Moderna Therapeutics Inc Polynucleotides encoding low density lipoprotein receptor
WO2019035938A1 (en) 2017-08-16 2019-02-21 Elstar Therapeutics, Inc. Multispecific molecules that bind to bcma and uses thereof
US20210145778A1 (en) * 2018-01-01 2021-05-20 Orbicular Pharmaceutical Technologies Pvt. Ltd. Stable Liquid Compositions of Melphalan

Citations (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4444887A (en) 1979-12-10 1984-04-24 Sloan-Kettering Institute Process for making human antibody producing B-lymphocytes
EP0239400A2 (en) 1986-03-27 1987-09-30 Medical Research Council Recombinant antibodies and methods for their production
US4716111A (en) 1982-08-11 1987-12-29 Trustees Of Boston University Process for producing human antibodies
WO1991009967A1 (en) 1989-12-21 1991-07-11 Celltech Limited Humanised antibodies
WO1991010741A1 (en) 1990-01-12 1991-07-25 Cell Genesys, Inc. Generation of xenogeneic antibodies
WO1992022653A1 (en) 1991-06-14 1992-12-23 Genentech, Inc. Method for making humanized antibodies
EP0519596A1 (en) 1991-05-17 1992-12-23 Merck & Co. Inc. A method for reducing the immunogenicity of antibody variable domains
EP0592106A1 (en) 1992-09-09 1994-04-13 Immunogen Inc Resurfacing of rodent antibodies
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5565332A (en) 1991-09-23 1996-10-15 Medical Research Council Production of chimeric antibodies - a combinatorial approach
WO1996034096A1 (en) 1995-04-28 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1996033735A1 (en) 1995-04-27 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1998016654A1 (en) 1996-10-11 1998-04-23 Japan Tobacco, Inc. Production of a multimeric protein by cell fusion method
WO1998024893A2 (en) 1996-12-03 1998-06-11 Abgenix, Inc. TRANSGENIC MAMMALS HAVING HUMAN IG LOCI INCLUDING PLURAL VH AND Vλ REGIONS AND ANTIBODIES PRODUCED THEREFROM
US5814318A (en) 1990-08-29 1998-09-29 Genpharm International Inc. Transgenic non-human animals for producing heterologous antibodies
WO1998046645A2 (en) 1997-04-14 1998-10-22 Micromet Gesellschaft Für Biomedizinische Forschung Mbh Method for the production of antihuman antigen receptors and uses thereof
WO1998050433A2 (en) 1997-05-05 1998-11-12 Abgenix, Inc. Human monoclonal antibodies to epidermal growth factor receptor
WO1999062526A2 (en) * 1998-06-05 1999-12-09 Mayo Foundation For Medical Education And Research Use of genetically engineered antibodies to cd38 to treat multiple myeloma
WO2006099875A1 (en) * 2005-03-23 2006-09-28 Genmab A/S Antibodies against cd38 for treatment of multiple myeloma
EP1914242A1 (en) * 2006-10-19 2008-04-23 Sanofi-Aventis Novel anti-CD38 antibodies for the treatment of cancer

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB750155A (en) 1953-03-17 1956-06-13 Nat Res Dev Substituted alanines
US3032585A (en) 1954-12-03 1962-05-01 Nat Res Dev Process for the production of p-bis-(2-chloroethyl)-aminophenylalanine
US7223397B1 (en) 1999-01-07 2007-05-29 Research Development Foundation Potentiation of anti-CD38-Immunotoxin cytotoxicity
GB0221574D0 (en) 2002-09-17 2002-10-23 Isis Innovation Treatments
ES2541489T3 (en) 2004-02-06 2015-07-21 Morphosys Ag Human anti-CD38 antibodies and uses for them
PL2081595T3 (en) 2006-09-26 2019-11-29 Genmab As Anti-cd38 plus corticosteroids plus a non-corticosteroid chemotherapeutic for treating tumors
US20080092384A1 (en) * 2006-10-16 2008-04-24 Schaake Mark D Installation of Middle Bearing for a Crankshaft
EP2191841A1 (en) 2008-11-28 2010-06-02 Sanofi-Aventis Antitumor combinations containing antibodies recognizing specifically CD38 and vincristine
EP2191843A1 (en) 2008-11-28 2010-06-02 Sanofi-Aventis Antitumor combinations containing antibodies recognizing specifically CD38 and cyclophosphamide
EP2191840A1 (en) 2008-11-28 2010-06-02 Sanofi-Aventis Antitumor combinations containing antibodies recognizing specifically CD38 and melphalan

Patent Citations (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4444887A (en) 1979-12-10 1984-04-24 Sloan-Kettering Institute Process for making human antibody producing B-lymphocytes
US4716111A (en) 1982-08-11 1987-12-29 Trustees Of Boston University Process for producing human antibodies
EP0239400A2 (en) 1986-03-27 1987-09-30 Medical Research Council Recombinant antibodies and methods for their production
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5585089A (en) 1988-12-28 1996-12-17 Protein Design Labs, Inc. Humanized immunoglobulins
WO1991009967A1 (en) 1989-12-21 1991-07-11 Celltech Limited Humanised antibodies
WO1991010741A1 (en) 1990-01-12 1991-07-25 Cell Genesys, Inc. Generation of xenogeneic antibodies
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5814318A (en) 1990-08-29 1998-09-29 Genpharm International Inc. Transgenic non-human animals for producing heterologous antibodies
EP0519596A1 (en) 1991-05-17 1992-12-23 Merck & Co. Inc. A method for reducing the immunogenicity of antibody variable domains
WO1992022653A1 (en) 1991-06-14 1992-12-23 Genentech, Inc. Method for making humanized antibodies
US5565332A (en) 1991-09-23 1996-10-15 Medical Research Council Production of chimeric antibodies - a combinatorial approach
EP0592106A1 (en) 1992-09-09 1994-04-13 Immunogen Inc Resurfacing of rodent antibodies
US5639641A (en) 1992-09-09 1997-06-17 Immunogen Inc. Resurfacing of rodent antibodies
WO1996033735A1 (en) 1995-04-27 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1996034096A1 (en) 1995-04-28 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1998016654A1 (en) 1996-10-11 1998-04-23 Japan Tobacco, Inc. Production of a multimeric protein by cell fusion method
WO1998024893A2 (en) 1996-12-03 1998-06-11 Abgenix, Inc. TRANSGENIC MAMMALS HAVING HUMAN IG LOCI INCLUDING PLURAL VH AND Vλ REGIONS AND ANTIBODIES PRODUCED THEREFROM
WO1998046645A2 (en) 1997-04-14 1998-10-22 Micromet Gesellschaft Für Biomedizinische Forschung Mbh Method for the production of antihuman antigen receptors and uses thereof
WO1998050433A2 (en) 1997-05-05 1998-11-12 Abgenix, Inc. Human monoclonal antibodies to epidermal growth factor receptor
WO1999062526A2 (en) * 1998-06-05 1999-12-09 Mayo Foundation For Medical Education And Research Use of genetically engineered antibodies to cd38 to treat multiple myeloma
WO2006099875A1 (en) * 2005-03-23 2006-09-28 Genmab A/S Antibodies against cd38 for treatment of multiple myeloma
EP1914242A1 (en) * 2006-10-19 2008-04-23 Sanofi-Aventis Novel anti-CD38 antibodies for the treatment of cancer
WO2008047242A2 (en) 2006-10-19 2008-04-24 Sanofi-Aventis Novel anti-cd38 antibodies for the treatment of cancer

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
ELLIS JONATHAN H ET AL: "Engineered anti-CD38 monoclonal antibodies for immunotherapy of multiple myeloma", JOURNAL OF IMMUNOLOGY, AMERICAN ASSOCIATION OF IMMUNOLOGISTS, US, vol. 155, no. 2, 1 January 1995 (1995-01-01), pages 925 - 937, XP002146232, ISSN: 0022-1767 *
F.M. SCHABEL ET AL.: "Cancer Drug Development, Part B, Methods in Cancer Research", vol. 17, 1979, ACADEMIC PRESS INC., pages: 3 - 51
PADLAN E. A., MOLECULAR IMMUNOLOGY, vol. 28, no. 4/5, 1991, pages 489 - 498
PEIPP M ET AL: "FULLY HUMAN CD38 ANTIBODIES EFFICIENTLY TRIGGER ADCC AND CDC OF MULTIPLE MYELOMA AND PLASMA CELL LEUKEMIA CELLS", INTERNET CITATION, XP002473215, Retrieved from the Internet <URL:http://www.genmab.com/upload/poster_ash_2005_monday_05-12-2005.pdf> [retrieved on 20080318] *
PEIPP M ET AL: "Fully human CD38 antibodies efficiently trigger ADCC of multiple myeloma cell lines and primary tumor cells", BIOSIS,, 1 January 1900 (1900-01-01), XP002389878 *
PEIPP M ET AL: "FULLY HUMAN CD38 ANTIBODIES EFFICIENTLY TRIGGER ADCC OF MULTIPLE MYELOMA CELL LINES AND PRIMARY TUMOR CELLS", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 106, no. 11, PART 01, 1 November 2005 (2005-11-01), pages 944A,ABSTRACTNO.3377, XP009069301, ISSN: 0006-4971 *
ROGUSKA M.A. ET AL., PNAS, vol. 91, 1994, pages 969 - 973
STUDNICKA G. M. ET AL., PROTEIN ENGINEERING, vol. 7, no. 6, 1994, pages 805 - 814
T.H. CORBETT ET AL., CANCER, vol. 40, 1977, pages 2660 - 2680

Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017048208A (en) * 2010-09-27 2017-03-09 モルフォシス・アー・ゲー Anti-cd38 antibody and lenalidomide or bortezomib for treatment of multiple myeloma and nhl
US9765152B2 (en) 2010-09-27 2017-09-19 Morphosys Ag Method for the treatment of multiple myeloma or non-Hodgkins lymphoma with anti-CD38 antibody and bortezomib or carfilzomib
WO2012041800A1 (en) 2010-09-27 2012-04-05 Morphosys Ag Anti-cd38 antibody and lenalidomide or bortezomib for the treatment of multiple myeloma and nhl
JP2013542191A (en) * 2010-09-27 2013-11-21 モルフォシス・アー・ゲー Anti-CD38 antibody and lenalidomide or bortezomib for treatment of multiple myeloma and NHL
US10308722B2 (en) 2010-09-27 2019-06-04 Morphosys Ag Method for the treament of multiple myeloma or non-hodgkins lymphoma with anti-CD38 antibody in combination with thalidomine, lenalidomids, or pomalidomide
US9289490B2 (en) 2010-09-27 2016-03-22 Morphosys Ag Combinations and uses thereof
US8877899B2 (en) 2010-09-27 2014-11-04 Morphosys Ag Anti-CD38 antibody and lenalidomide or bortezomib for the treatment of multipe myeloma and NHL
JP2014502280A (en) * 2010-12-10 2014-01-30 サノフイ Anti-tumor combination comprising antibody specifically recognizing CD38 and bortezomib
EP3412311A1 (en) * 2010-12-10 2018-12-12 Sanofi Antitumor combinations containing antibodies recognizing specifically cd38 and bortezomib
EA026406B1 (en) * 2010-12-10 2017-04-28 Санофи Antitumor combinations containing antibodies recognizing specifically cd38 and bortezomib
US9314522B2 (en) 2010-12-10 2016-04-19 Sanofi Antitumors combinations containing antibodies recognizing specifically CD38 and bortezomib
KR101905208B1 (en) * 2010-12-10 2018-10-05 사노피 Antitumor combinations containing antibodies recognizing specifically cd38 and bortezomib
CN103282050A (en) * 2010-12-10 2013-09-04 赛诺菲 Antitumor combinations containing antibodies recognizing specifically CD38 and bortezomib
WO2012076663A1 (en) * 2010-12-10 2012-06-14 Sanofi Antitumor combinations containing antibodies recognizing specifically cd38 and bortezomib
AU2011340472B2 (en) * 2010-12-10 2015-02-12 Sanofi Antitumor combinations containing antibodies recognizing specifically CD38 and bortezomib
US11434304B2 (en) 2010-12-30 2022-09-06 Takeda Pharmaceutical Company Limited Anti-CD38 antibodies
US10494444B2 (en) 2010-12-30 2019-12-03 Takeda Pharmaceutical Company Limited Anti-CD38 antibodies
AU2013322806B2 (en) * 2012-09-25 2017-11-30 Morphosys Ag Combinations and uses thereof
AU2013322806C1 (en) * 2012-09-25 2018-03-08 Morphosys Ag Combinations and uses thereof
RU2650618C2 (en) * 2012-09-25 2018-04-16 МорфоСис АГ Combinations and their application
CN104684552B (en) * 2012-09-25 2018-08-07 莫佛塞斯公司 Combination and application thereof
US9579378B2 (en) 2012-09-25 2017-02-28 Morphosys Ag Combinations and uses thereof
WO2014048921A1 (en) 2012-09-25 2014-04-03 Morphosys Ag Combinations and uses thereof
WO2015066450A1 (en) 2013-10-31 2015-05-07 Sanofi Specific anti-cd38 antibodies for treating human cancers
EP3805266A1 (en) 2013-10-31 2021-04-14 Sanofi Specific anti-cd38 antibodies for treating human cancers
US10556961B2 (en) 2014-02-28 2020-02-11 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of acute lymphoblastic leukemia
US10800851B2 (en) 2014-02-28 2020-10-13 Janssen Biotech, Inc. Combination therapies with anti-CD38 antibodies
US11713355B2 (en) 2014-02-28 2023-08-01 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of acute lymphoblastic leukemia
US12060432B2 (en) 2014-02-28 2024-08-13 Janssen Biotech, Inc. Combination therapies with anti-CD38 antibodies
US10617757B2 (en) 2014-08-08 2020-04-14 The Regents Of The University Of California Methods for treating multiple myeloma
US10604580B2 (en) 2014-09-09 2020-03-31 Janssen Biotech, Inc. Combination therapies with anti-CD38 antibodies
US10793630B2 (en) 2014-12-04 2020-10-06 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of acute myeloid leukemia
US12091466B2 (en) 2015-05-20 2024-09-17 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of light chain amyloidosis and other CD38-positive hematological malignancies
US10766965B2 (en) 2015-05-20 2020-09-08 Janssen Biotech, Inc. Anti-CD38 antibodies for treatment of light chain amyloidosis and other CD38-positive hematological malignancies
US10668149B2 (en) 2015-06-22 2020-06-02 Janssen Biotech, Inc. Combination therapies for heme malignancies with anti-CD38 antibodies and survivin inhibitors
US11021543B2 (en) 2015-06-24 2021-06-01 Janssen Biotech, Inc. Immune modulation and treatment of solid tumors with antibodies that specifically bind CD38
US11708420B2 (en) 2015-11-03 2023-07-25 Janssen Biotech, Inc. Subcutaneous formulations of anti-CD38 antibodies and their uses
US10781261B2 (en) 2015-11-03 2020-09-22 Janssen Biotech, Inc. Subcutaneous formulations of anti-CD38 antibodies and their uses
US11732051B2 (en) 2015-11-03 2023-08-22 Janssen Biotech, Inc. Subcutaneous formulations of anti-CD38 antibodies and their uses
US10385135B2 (en) 2015-11-03 2019-08-20 Janssen Biotech, Inc. Subcutaneous formulations of anti-CD38 antibodies and their uses
US11708419B2 (en) 2015-11-03 2023-07-25 Janssen Biotech, Inc. Subcutaneous formulations of anti-CD38 antibodies and their uses
US11566079B2 (en) 2015-11-03 2023-01-31 Janssen Biotech, Inc. Subcutaneous formulations of anti-CD38 antibodies and their uses
US11618787B2 (en) 2017-10-31 2023-04-04 Janssen Biotech, Inc. Methods of treating high risk multiple myeloma
WO2020187718A1 (en) 2019-03-15 2020-09-24 Morphosys Ag Anti-cd38 antibodies and pharmaceutical compositions thereof for the treatment of autoantibody-mediated autoimmune disease
US11655302B2 (en) 2019-06-10 2023-05-23 Sanofi Anti-CD38 antibodies and formulations
WO2021113739A1 (en) 2019-12-05 2021-06-10 Thomas Ballet Formulations of anti-cd38 antibodies for subcutaneous administration
WO2022152823A1 (en) 2021-01-14 2022-07-21 Morphosys Ag Anti-cd38 antibodies and their uses
WO2022184676A1 (en) 2021-03-01 2022-09-09 Morphosys Ag Anti-cd38 antibodies for use in the treatment of antibody-mediated transplant rejection
WO2023001804A1 (en) 2021-07-19 2023-01-26 Morphosys Ag Treatment of anti-pla2r autoantibody-mediated membranous nephropathy

Also Published As

Publication number Publication date
US9259406B2 (en) 2016-02-16
AU2009321249A1 (en) 2010-06-03
PE20120340A1 (en) 2012-04-17
TN2011000232A1 (en) 2012-12-17
CN102264385A (en) 2011-11-30
EA201100864A1 (en) 2011-12-30
HN2011001417A (en) 2014-01-13
SG171820A1 (en) 2011-07-28
IL213116A0 (en) 2011-07-31
TWI454260B (en) 2014-10-01
MA32896B1 (en) 2011-12-01
KR20110096550A (en) 2011-08-30
UA107069C2 (en) 2014-11-25
MY164577A (en) 2018-01-15
ME01136B (en) 2013-03-20
JP6148696B2 (en) 2017-06-14
BRPI0921864B1 (en) 2022-11-16
UY32263A (en) 2010-06-30
JP2017141233A (en) 2017-08-17
EP2370094A1 (en) 2011-10-05
JP2015205890A (en) 2015-11-19
CO6440557A2 (en) 2012-05-15
AU2009321249B2 (en) 2016-06-09
CA2744990A1 (en) 2010-06-03
TW201023855A (en) 2010-07-01
CR20110280A (en) 2011-09-20
ECSP11011062A (en) 2011-07-29
CA2744990C (en) 2019-05-07
PA8850101A1 (en) 2010-07-27
EP2191840A1 (en) 2010-06-02
JP2012510461A (en) 2012-05-10
ZA201103925B (en) 2012-09-26
NZ593027A (en) 2012-12-21
EA026867B1 (en) 2017-05-31
HK1164165A1 (en) 2012-09-21
BRPI0921864A2 (en) 2018-10-09
IL213116B (en) 2018-11-29
MX2011005670A (en) 2011-09-30
AR074219A1 (en) 2010-12-29
KR101733252B1 (en) 2017-05-08
US20110274686A1 (en) 2011-11-10
SV2011003924A (en) 2011-10-07
CL2011001254A1 (en) 2012-01-27
MX342625B (en) 2016-10-06
CN102264385B (en) 2015-05-20
NI201100105A (en) 2011-12-13

Similar Documents

Publication Publication Date Title
AU2009321249B2 (en) Antitumor combinations containing antibodies recognizing specifically CD38 and melphalan
AU2009321251B2 (en) Antitumor combinations containing antibodies recognizing specifically CD38 and cytarabine
AU2009321252B2 (en) Antitumor combinations containing antibodies recognizing specifically CD38 and cylophosphamide
US8633301B2 (en) Antitumor combinations containing antibodies recognizing specifically CD38 and vincristine
CA2820382C (en) Antitumor combinations containing antibodies recognizing specifically cd38 and bortezomib

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200980148094.4

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09775302

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2003/KOLNP/2011

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2009321249

Country of ref document: AU

Ref document number: 593027

Country of ref document: NZ

Ref document number: 2009775302

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 213116

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2744990

Country of ref document: CA

Ref document number: 001107-2011

Country of ref document: PE

Ref document number: CR2011-000280

Country of ref document: CR

ENP Entry into the national phase

Ref document number: 0132511

Country of ref document: KE

WWE Wipo information: entry into national phase

Ref document number: 2011001254

Country of ref document: CL

Ref document number: 2011538092

Country of ref document: JP

Ref document number: 11065644

Country of ref document: CO

Ref document number: 12011501050

Country of ref document: PH

Ref document number: MX/A/2011/005670

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2009321249

Country of ref document: AU

Date of ref document: 20091127

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: DZP2011000393

Country of ref document: DZ

ENP Entry into the national phase

Ref document number: 20117014746

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 201100864

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: 13130862

Country of ref document: US

ENP Entry into the national phase

Ref document number: PI0921864

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20110527