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WO2013067581A1 - Traitement du cancer - Google Patents

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Publication number
WO2013067581A1
WO2013067581A1 PCT/AU2012/001368 AU2012001368W WO2013067581A1 WO 2013067581 A1 WO2013067581 A1 WO 2013067581A1 AU 2012001368 W AU2012001368 W AU 2012001368W WO 2013067581 A1 WO2013067581 A1 WO 2013067581A1
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Prior art keywords
individual
disease
treatment
adc
lymphoma
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Inventor
Richard B LOCK
Hernan CAROL
Barbara SZYMANSKA
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Childrens Cancer Institute Australia for Medical Research
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Childrens Cancer Institute Australia for Medical Research
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68033—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6867—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from a cell of a blood cancer
    • 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

Definitions

  • the invention relates to the treatment of cancer, particularly to induction therapy of leukemia and lymphoma. Background of the invention
  • Acute lymphoblastic leukemia is the most common childhood malignancy, constituting approximately 80% of pediatric leukemias and nearly one-third of all childhood cancers 1 .
  • advances 1 in the treatment of pediatric ALL have resulted in cure rates increasing from ⁇ 10% to around 85% 2,3 .
  • This improvement in patient outcome has principally resulted from the development of combination chemotherapy protocols, intensification of treatment for high-risk patients, and improvements in supportive care, rather than through the introduction of new drugs.
  • VCR vincristine
  • L-ASNase L-asparaginase
  • CR complete remission
  • the invention seeks to address one or more limitations or problems applying to the treatment of neoplastic diseases including leukemias and lymphomas, and in one embodiment provides a method of treating an individual having a disease characterised by the presence of neoplastic CD 19 positive cells including the step of:
  • an antibody drug conjugate ADC
  • ADC antibody drug conjugate
  • an ADC in the form of an anti-CD 19 antibody conjugated to a cytotoxic drug for the treatment of an individual having a disease characterised by the presence of neoplastic CD 19 positive cells, wherein the individual has received induction therapy for treatment of the disease.
  • a kit or composition for the treatment of an individual having a disease characterised by the presence of CD19 positive cells including:
  • an ADC in the form of an anti-CD 19 antibody conjugated to a cytotoxic drug
  • a method of treating an individual having a disease characterised by the presence of neoplastic CD 19 positive cells including the steps of:
  • a maytansinoid to an individual who has received an induction therapy for the treatment of a disease characterised by the presence of neoplastic cells, wherein the induction therapy is in the form of a treatment including a vinca alkaloid; thereby treating the individual for the disease.
  • SAR3419 exerts significant in vivo single-agent efficacy against B-Iineage pediatric ALL xenografts.
  • NOD/SCID mice engrafted with xenografts derived from: (A-C) BCP-ALL, ALL-2 (A), ALL-3 (B) or ALL- 17 (C); T-ALL, ALL-8 (D); or MLL, MLL-3 (E).
  • A-C BCP-ALL, ALL-2 (A), ALL-3 (B) or ALL- 17 (C); T-ALL, ALL-8 (D); or MLL, MLL-3
  • Following establishment of disease mice were randomized and treated with vehicle (dashed lines) or 10 mg/kg SAR3419 (solid lines) once a week for 3 weeks. Response to treatment was monitored by weekly enumeration of the %huCD45+ cells in the PB of individual mice (left panel).
  • EFS is represented by Kaplan-Meier analysis (right panel).
  • FIG. 1 Summary of SAR3419 single-agent efficacy against pediatric ALL xenografts.
  • A Description of xenografts, table of median EFS values for control versus SAR3419 treated mice, LGD values, statistical analyses (logrank) and median ORMs.
  • B "COMPARE-like" plot of the midpoint difference representing the median ORM of xenografts. A score of -5 to 0 indicates that an objective response was not achieved for a particular xenograft, whereas a score of >0 to 5 indicates an Objective Response. Red bars indicate that the EFS was significantly different between control and treated mice. Blue bars indicate no significant difference.
  • CD19 expression correlates with in vivo response to SAR3419.
  • A CD 19 gene expression expressed in heat map format. Expression levels were normalized to the mean (defined as 0), and relative expression depicted according to the logarithmic scale.
  • B Representation of CD 19 surface expression on three different xenografts (gray isotype control, green ALL- 16, blue ALL-3, red ALL- 19).
  • C Regression curves and 95% confidence intervals of CD 19 mRNA and protein expression correlated with median ORMs (left panel) and LGDs (right panel).
  • SAR3419 is effective against BCP-ALL xenografts in vivo over a broad dose range.
  • Mice engrafted with (A) ALL-4 or (B) ALL- 19 were treated with vehicle control or SAR3419 at 10 mg/kg, 7.5 mg/kg, 5 mgAcg, 2.5 mg/kg, 1.0 mg/kg or naked Ab - HuB4.
  • Response to treatment and disease progression were monitored by weekly enumeration of the proportion of %huCD45+ cells in the PB of individual mice (left panel), and Kaplan-Meier analysis of EFS (right panel). Gray arrows indicate treatment time points.
  • FIG. 1 Summary of SAR3419 dose response and VXL combination efficacy studies.
  • A Median EFS values of control and treated groups of mice, LGD values, statistical analyses (logrank) and median ORMs.
  • B "COMPARE-like" plot of the midpoint difference representing the median ORM of xenografts. See legend to Figure 2 for additional details.
  • C ORMs of individual mice in each treatment group.
  • FIG. 6 Efficacy of SAR3419 against BCP-ALL xenografts following remission induction with VXL therapy.
  • the VXL treatment period is indicated by the shaded area, and SAR3419 treatment time points are marked by gray arrows.
  • Left panels represents the %huCD45+ cells in PB of individual mice, and the right panels show Kaplan-Meier plots of EFS.
  • VXL/SAR3419 extended treatment events due to morbidity in the absence of hematolymphoid relapse are shown as vertical black lines on the gray solid lines in the right panels.
  • C %huCD45+ cells in various tissues at necropsy. VXL/SAR3419 times 3 weeks (black bars), VXL/SAR3419 extended treatment (white bars).
  • PB peripheral blood
  • SP spleen
  • BM bone marrow
  • LN lymph node
  • Liv liver
  • Lu lung
  • KD kidney
  • BR brain
  • SF spinal fluid.
  • FIG. 8 Single agent efficacy of SAR3419.
  • NOD/SCID mice engrafted with MLLs: (A) MLL-8; (B) MLL-14; (C) or T-ALL: ALL-16 were treated with vehicle (dashed lines) or 10 mg/kg SAR3419 (solid lines) once a week for 3 weeks (treatment time points are indicated by gray arrows).
  • the response to treatment was monitored by weekly measurements of the %huCD45+ cells in PB of individual mice (left panel).
  • the EFS time to reach 25% of leukemia cells in PB was represented by Kaplan-Meier plots (right panel). Gray arrows indicate treatment time points.
  • SAR3419 is comprised of the maytansinoid DM4 conjugated to the antibody HuB4.
  • a method of treating an individual having a disease characterised by the presence of neoplastic CD19 positive cells including the steps of:
  • an antibody drug conjugate ADC
  • the ADC in the form of an anti-CD 19 antibody conjugated to a cytotoxic drug; thereby treating the individual for the disease.
  • the cytotoxic drug is typically a maytansinoid, although other cytotoxic drugs include taxanes, tomaymycine derivatives, leptomycin derivatives, CC01065 analogues, and other drugs all of which are generally well known to the skilled worker.
  • the cytotoxic agent is DM4.
  • the antibody may be any antibody that selectively or specifically binds to CD 19.
  • One example of an antibody is huB4, or an antibody that is capable of competing with huB4 for binding to CD 19.
  • the antibody is a monoclonal antibody or fragment thereof that selectively or specifically binds to CD19.
  • the latter include a Fab, a Fab', a F(ab') 2 , a Fv, a single- chain Fv, or a single variable domain.
  • the ADC is SAR3419.
  • the ADC is administered by continuous weekly infusion, for a period of at least about 3 to 6 months following induction therapy. This is generally a once a week iiifusion, although in certain embodiments, the infusion may be given more often that once a week.
  • the time period for infusion is expected to be no more than 5 years. In particular, as shown herein, the likelihood of preventing relapse of disease is minimised where continuous weekly infusion is provided over a longer period of time.
  • the ADC is administered after the induction therapy has been completed, although in some embodiments the ADC may be administered before completion of induction therapy, or during induction therapy.
  • the individual may contains neoplastic cells that are resistant to the induction therapy at the time of administration of the ADC.
  • the ADC treatment is effective for preventing relapse of cancer in individuals in which the cancer is known to be resistant to induction therapy.
  • neoplastic cells may not be detectable, or there may be minimal symptoms of disease in the individual at the time of treatment with the ADC.
  • the ADC treatment is included as a routine therapeutic step on completion of the induction therapy to safeguard against undetectable induction therapy -resistant neoplastic cells recurring.
  • an ADC in the form of an anti-CD 19 antibody conjugated to a cytotoxic drug for the treatment of an individual having a disease characterised by the presence of neoplastic CD 19 positive cells, wherein the individual has received induction therapy for treatment of the disease.
  • kits or compositions for the treatment of an individual having a disease characterised by the presence of CD 19 positive cells including: - an ADC in the form of an anti-CD 19 antibody conjugated to a cytotoxic drug;
  • the ADC is SAR3419.
  • the disease is acute lymphocytic leukemia (ALL).
  • ALL acute lymphocytic leukemia
  • the inventors have found that the clinical outcome of treatment of ALL in individuals who have received induction therapy and ADC therapy is greater than that observed for. treatment by induction therapy or ADC therapy alone. Therefore, the inventors have identified synergy arising from the combination of these administrations for treatment of ALL.
  • induction therapy includes therapy with a drug combination including a vinca alkaloid.
  • Vinca alkaloids target cytoskeletal apparatus including tubulin. It is a particularly surprising finding of the invention that cells that have developed resistance to an induction therapy that targets the cytoskeleton remain vulnerable to other cytotoxic agents that target the same cytoskeleton apparatus. As described herein, the inventors have found that resistance that may arise to vinca alkaloid-based induction therapy does not confer resistance to other cytotoxic agents, including those described below, that also target the cytoskeleton.
  • the vinca alkaloid is vincristine and in a particularly preferred form the induction therapy is therapy with a drug combination including vincristine, a glucocorticoid (eg dexamethasone) and L-aspariginase (VXL).
  • a drug combination including vincristine, a glucocorticoid (eg dexamethasone) and L-aspariginase (VXL).
  • induction therapy of ALL patients or re-induction post relapse can include vincristine plus a glucocorticoid (dexamethasone, prednisone or prednisolone) plus L- asparaginase with or without an anthracycline (usually daunorubicin).
  • Another regimen for re- induction for ALL includes etoposide plus cyclophosphamide (CE).
  • the objective or outcome of treatment may be to reduce the number of cancer cells; reduce the primary tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the disorder.
  • the method of the invention may enable certain clinical outcomes to be obtained. Desirably these may be one or more of the following: improved duration of survival; improved time to disease progression; improved response rates (RR); improved duration of response; improved quality of life.
  • Efficacy of treatment can be measured by assessing the duration of survival, time to disease progression, the response rates (RR), duration of response, and/or quality of life.
  • the method is particularly useful for extending time to disease progression.
  • the method is particularly useful for extending survival of the human, including overall survival as well as progression free survival.
  • the method is particularly useful for providing a complete response to therapy whereby all signs of cancer in response to treatment have disappeared. This does not always mean the cancer has been cured.
  • the method is particularly useful for providing a partial response to therapy whereby there has been a decrease in the size of one or more tumors or lesions, or in the extent of cancer in the body, in response to treatment.
  • Effective doses of the compositions of the present invention, for treatment of disorders, as described herein, vary depending upon many different factors, including means of administration, target site, physiological state of the patient, other medications administered, and whether treatment is prophylactic or therapeutic. Treatment dosages may be titrated using routine methods known to those of skill in the art to optimize safety and efficacy.
  • the dosage can range, e.g., from about 0.0001 to 100 mg/kg, and more usually 0.01 to 5 mg/kg (e.g., 0.02 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 0.75 mg/kg, 1 mg/kg, 2 mg/kg, etc.), of the host body weight.
  • dosages can be 1 mg/kg body weight or 10 mg kg body weight or within the range of 1-10 mg/kg, preferably at least 1 mg/kg.
  • Doses intermediate in the above ranges are also intended to be within the scope of the invention.
  • Subjects can be administered such doses daily, on alternative days, weekly or according to any other schedule determined by empirical analysis.
  • An exemplary treatment entails administration in multiple dosages over a prolonged period, for example, of at least six months. Additional exemplary treatment regimes entail administration once per every two weeks or once a month or once every 3 to 6 months. Exemplary dosage schedules include 1-10 mg/kg or 15 mg/kg on consecutive days, 30 mg kg on alternate days or 60 mg/kg weekly. In some methods, two or more antigen binding sites with different binding specificities are administered simultaneously, in which case the dosage of each antigen binding site administered falls within the ranges indicated. In another embodiment, the invention provides a method of treating an individual having a disease characterised by the presence of neoplastic CD 19 positive cells including the step of:
  • the invention provides a method of treating an individual having a disease characterised by the presence of neoplastic cells including the step of:
  • the maytansinoid is DM4, although other maytansinoids may be used in certain embodiments as described herein.
  • maytansmoid therapy is associated with problems of acute toxicity. Therefore in a preferred form of the invention, the maytansinoid is adapted to minimise acute toxicity of the maytansinoid. This could be done by encapsulating the maytansinoid, for example by liposomes or other related technology.
  • the acute toxicity issue is resolved by targeting the maytansinoid to an antibody, thereby facilitating targeting of the antibody to neoplastic cells that have an antigen to which the antibody may bind.
  • any antibody may be used in these embodiments of the invention, provided that the antibody binds to a biomarker of a cancer cell.
  • the markers may be CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD37, CD53, CD72, CD74, CD75, CD77, CD79a, CD79b, CD80, CD81, CD82, CD83, CD84, CD85, and CD86 leukocyte surface markers.
  • the antibody is an anti-CD 19 antibody.
  • the present invention provides for methods of treating neoplastic cells expressing the CD 19 molecule on their cell surface.
  • the neoplastic cells expressing CD 19 can be Leukemias or Lymphomas.
  • the Leukemia may be an acute lymphocytic leukemia (ALL).
  • ALL can be a B-cell precursor acute Leukemia (preB-ALL also known as BCP-ALL).
  • the ALL may be an acute B-cell lymphoblastic leukemia (B-).
  • the acute leukemia may be an acute myelogenous leukemia (AML).
  • AML acute myelogenous leukemia
  • CD 19 positive leukemias have the t(9;22)(q34;ql 1) translocation (also known as the Philadephia chromosome).
  • the ALL or AML can be characterised by the presence of MLL gene rearrangements, in particular the t(l I ;19)(q23;pl3.3) and/or t(4:l l),t(9:l l) translocations.
  • the translocations result in the fusion of the MLL gene gene to ENL (MLL-ENL leukemia).
  • the invention also provides for the treatment of CD 19 positive lymphomas, in particular, non-Hodgkin's lymphoma.
  • the invention provides for treatment of CD 19 positive lymphomas which include but is not limited to the following types: small lymphocytic lymphoma, lymphoplasmacytoid/lymphoplasmacytic lymphoma (such as Walenstrom macroglobulinemia), mantle cell lymphoma, follicular lymphoma, marginal B-cell lymphoma, extranodal B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), diffuse large B-cell lymphoma, plasma cell neoplasms, Burkitt's lymphoma and anaplastic large cell lymphoma.
  • small lymphocytic lymphoma such as Walenstrom macroglobulinemia
  • mantle cell lymphoma such as Walenstrom macroglobulinemia
  • follicular lymphoma marginal B-cell lymphoma
  • the present invention provides for methods of treating neoplastic cells which are resistant to treatment with vinca alkaloids, especially vincristin, or to drug combinations that include vincristine, such as vincristine, a glucocorticoid (eg dexamethasone) and L-aspariginase (herein, VXL).
  • vincristine such as vincristine, a glucocorticoid (eg dexamethasone) and L-aspariginase (herein, VXL).
  • the invention provides for methods of treating neoplastic cells which are responsive to treatment with vinka alkaloids, for example VXL.
  • the invention provides for the treatment of pediatric leukemias and lymphomas of the kind mentioned above.
  • induction therapy may be given with a goal of decreasing the number of neoplastic cells to an undetectable level and/or restoring the production of normal cells. In some regimes, induction therapy may be followed by consolidation therapy (maintenance and post-remission), which aims to further eliminate any residual cancerous cells.
  • Common remission induction chemotherapy regimens for leukemia and lymphoma include administration of the agents identified in Table 1 : Table 1 : Commonly used chemotherapeutic agents used in the treatment of neoplasias as induction remission therapy
  • Adriamycin (doxorubicin), bleomycin
  • BEACOPP cyclophosphamide Oncovin (vincristine), Hodgkin's lymphoma
  • m-BACOD doxorubicin
  • cyclophosphamide Oncovin Non-Hodgkin lymphoma
  • MACOP-B Adriamycin doxorubicin
  • cyclophosphamide Non-Hodgkin lymphoma
  • Oncovin (vincristine), prednisone, bleomycin
  • the preferred multi-agent induction treatment is CHOP or CHOP-R.
  • the preferred multi-agent induction treatment is VXL.
  • the objective of the induction therapy is to reduce neoplastic cell number to a level which is undetectable.
  • Another approach is to obtain minimal residual disease (MDR).
  • the ADC includes a small, highly toxic drug (e.g., maytansinoids, taxanes, tomaymycin derivatives, leptomycin derivatives, and CC-1065 analogs) or any compound that results in the death of a cell, or induces cell death, or in some manner decreases cell viability.
  • Preferred cytotoxic agents include, for example, maytansinoids and maytansinoid analogs, taxoids, tomaymycin derivatives, leptomycin derivatives, CC-1065 and CC-1065 analogs, dolastatin and dolastatin analogs, as defined below. These cytotoxic agents may be conjugated to the antibodies, antibodies fragments, functional equivalents, improved antibodies and their analogs as disclosed herein
  • the cytotoxic conjugates may be prepared by in vitro methods.
  • a linking group is used.
  • Suitable linking groups are well known in the art and include disulfide groups, thioether groups, acid labile groups, photolabile groups, peptidase labile groups and esterase labile groups.
  • Preferred linking groups are disulfide groups and thioether groups.
  • conjugates can be constructed using a disulfide exchange reaction or by forming a thioether bond between the antibody and the drug or prodrug.
  • cytotoxic agents that may be used in the present invention to form a cytotoxic conjugate
  • maytansinoids and maytansinoid analogs examples include maytansinol and maytansinol analogs.
  • Maytansinoids are drugs that inhibit microtubule formation and that are highly toxic to mammalian cells.
  • suitable maytansinol . analogues include those having a modified aromatic ring and those having modifications at other positions.
  • suitable maytansinoids are disclosed in U.S. Patent Nos. 4,424,219; 4,256,746; 4,294,757; 4,307,016; 4,313,946; 4,315,929; 4,331,598; 4,361 ,650; 4,362,663; 4,364,866; 4,450,254; 4,322,348; 4,371 ,533; 6,333,410; 5,475,092; 5,585,499; and 5,846,545.
  • Suitable analogues of maytansinol having a modified aromatic ring include: (1) C-19-dechlofo (U.S. Pat. No. 4,256,746) (prepared by LAH reduction of ansamytocin
  • the cytotoxic conjugates of the present invention may utilize the thiol-containing maytansinoid (DM1), formally termed N2'-deacetyl-N2'-(3-mercapto-l- oxopropyl)-maytansine, as the cytotoxic agent.
  • DM1 is represented by the following structural formula (I):
  • the cytotoxic conjugates of the present invention utilize the thiol-containing maytansinoid N2 ' -deacetyl-N-2 ' (4-methyl-4-mercapto- 1 -oxopentyO- maytansine as the cytotoxic agent.
  • DM4 is represented by the following structural formula (II):
  • maytansines including thiol and disulfide- containing maytansinoids bearing a mono or di-alkyl substitution on the carbon atom bearing the sulfur atom
  • maytansines including thiol and disulfide- containing maytansinoids bearing a mono or di-alkyl substitution on the carbon atom bearing the sulfur atom
  • maytansines including thiol and disulfide- containing maytansinoids bearing a mono or di-alkyl substitution on the carbon atom bearing the sulfur atom
  • These include a maytansinoid having, at C-3, C-14 hydroxymethyl, C- 15 hydroxy, or C-20 desmethyl, an acylated amino acid side chain with an acyl group bearing a hindered sulfhydryl group, wherein the carbon atom of the acyl group bearing the thiol functionality has one or two substituents, said substituents being C3 ⁇ 4, C 2 Hs, linear or branched alkyl or alkenyl having
  • Such additional maytansines include compounds represented by formula (III):
  • R ⁇ and R 2 are each independently CH 3 , C2H5, linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocycloalkyl radical, and in addition R 2 can be
  • A, B, D are cycloalkyl or cycloalkenyl having 3 -10 carbon atoms, simple or substituted aryl or heterocyclic aromatic or heterocycloalkyl radical;
  • R3, R4, R5, Re, R7, Rs > R9, R11, and R 12 are each independently H, C3 ⁇ 4, C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocycloalkyl radical;
  • 1, m, n, o, p, q, r, s, and t are each independently 0 or an integer of from 1 to 5, provided that at least two of 1, m, n, o, p, q, r, s and t are not zero at any one time; and Z is H, SR or -COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocycloalkyl radical.
  • Preferred embodiments of formula (HI) include compounds of formula (III) wherein: Rj is H, R 2 is methyl and Z is H.
  • Ri and R 2 are methyl and Z is H.
  • Rj is H, R 2 is methyl, and Z is -SC3 ⁇ 4.
  • Rt and R 2 are methyl, and Z is -SCH 3 .
  • Such additional maytansines also include compounds represented by formula (IV-L), (IV- D), or (IV-D,L):
  • Y represents (CR 7 R8)i(CR 5 R6) m (CR 3 R4)nCRi R 2 SZ, wherein:
  • Ri and R 2 are each independently CH 3 , C2H5, linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, or heterocyclic aromatic or heterocycloalkyi radical, and in addition R 2 can be H;
  • R 3 , R4, R 5 , Re, R7 and R 8 are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, or heterocyclic aromatic or heterocycloalkyi radical;
  • n is independently an integer of from 1 to 5, and in addition n can be 0;
  • Z is H, SR or -COR wherein R is linear or branched alkyl or alkenyl having from 1 to 10 carbon atoms, cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocycloalkyi radical; and
  • Preferred embodiments of formulas (IV-L), (IV-D) and (IV-D,L) include compounds of formulas (IV-L), (IV-D) and (IV-D,L) wherein:
  • Ri is H
  • R 2 is methyl
  • R 5 , R 6 , R 7 , and Rs are each H
  • I and m are each 1
  • n is 0 and Z is
  • Ri and R 2 are methyl, R 5 , R 6 , R 7 , Rg are each H, I and m are 1 , n is 0, and Z is H.
  • Ri and R 2 are methyl, R 5 , Re, R , Rs are each H, I and m are 1 , n is 0, and Z is -SCH 3 .
  • the cytotoxic agent is represented by formula (IV-L).
  • Such additional maytansines also include compounds represented by formula (V):
  • Y represents (CR 7 R 8 )i(CR5R6)m(CR 3 R 4 )nCRiR 2 SZ, wherein; Ri and R 2 are each independently CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocycloalkyl radical, and in addition R 2 can be H;
  • R 3 , ⁇ , R 5 , Re, Rj, and R 8 are each independently H, CH 3s C2H5, linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, or heterocyclic aromatic or heterocycloalkyl radical;
  • n and n are each independently an integer of from 1 to 5, and in addition n can be 0; and Z is H, SR. or -COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocycloalkyl radical.
  • Preferred embodiments of formula (V) include compounds of formula (V) wherein:
  • Ri is H
  • R 2 is methyl
  • R 5 , R6, R 7 , and R 8 are each H
  • I and m are each 1
  • n is 0
  • Z is
  • Ri and R 2 are methyl, R 5 , R 7 , and Rg are each H, I and m are 1 ; n is 0; and Z is H.
  • Ri is H, R 2 is methyl, R R ⁇ , R 7 , and Rg are each H, I and m are each 1 , n is 0, and Z is -
  • Ri and R 2 are methyl, R 5 , R ⁇ > , R 7 , and R 8 are each H, I and m are 1 , n is 0, and Z is -
  • Such additional maytansines further include compounds represented by formula (Vl-L), (Vl-D), or (VI-D,L):
  • Y 2 represents (CR 7 R 8 ),(CR 5 R6) m (CR 3 R 4 )nCR, R 2 SZ 2 , wherein:
  • Ri and R 2 are each independently CH 3 , C 3 ⁇ 4, linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocycloalkyl radical, and in addition R 2 can be H;
  • R3, R4, R5, R 6 , R 7 and R 8 are each independently Hdon CH 3 , C 2 3 ⁇ 4, linear cyclic alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocycloalkyl radical;
  • n is independently an integer of from 1 to 5, and in addition n can be 0;
  • Z 2 is SR or COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocycloalkyl radical; and
  • Such additional maytansines also include compounds represented by formula (VII):
  • Ri and R 2 are each independently CH 3 , C 2 3 ⁇ 4, linear branched or alkyl or alkenyl having from 1 to 10 carbon atoms, cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocycloalkyl radical, and in addition R 2 can be H;
  • A, B and D each independently is cycloalkyl or cycloalkenyl having 3 to 10 carbon atoms, simple or substituted aryl, or heterocyclic aromatic or heterocycloalkyl radical;
  • R 3 , R4, R 5 , R$, R 7 , R 8 , R9, Ru, and Ri 2 are each independently H, C3 ⁇ 4, C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocycloalkyl radical;
  • Z 2 is SR or -COR, wherein R is linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 - 10 carbon atoms, or simple or substituted aryl or heterocyclic aromatic or heterocycloalkyl radical.
  • Preferred embodiments of formula (VII) include compounds of formula (VII) wherein: Ri is H and R 2 is methyl.
  • the above-mentioned maytansinoids can be conjugated to anti-CD 19 antibody or a homologue or fragment thereof, wherein the antibody is linked to the maytansinoid using the thiol or disulfide functionality that is present on the acyl group of an acylated amino acid side chain found at C-3, C-14 hydroxymethyl, C-15 hydroxy or C-20 desmethyl of the maytansinoid, and wherein the acyl group of the acylated amino acid side chain has its thiol or disulfide functionality located at a carbon atom that has one or two substituents, said substituents being CH3, C 2 Hs, linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocycloalkyl radical, and in addition one of the substituents can be H, and wherein the acyl group has
  • A, B, and D each independently is cycloalkyl or cycloalkenyl having 3 -10 carbon atoms, simple or substituted aryl, or heterocyclic aromatic or heterocycloalkyl radical;
  • R 3 , R4, R 5 , Re, R7, s, , Rn and Ri 2 are each independently H, CH 3 , C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocycloalkyl radical; and
  • 1, m, n, o, p, q, r, s, and t are each independently 0 or an integer of from 1 to 5, provided that at least two of I, m, n, o, p, q, r, s and t are non-not zero at any one time.
  • R[ is H and R 2 is methyl or Ri and R 2 are methyl.
  • An even more preferred conjugate of the present invention is the one that comprises the anti-CD 19 antibody or a homologue or fragment thereof, conjugated to a maytansinoid of formula (IX-L), (IX-D), or (IX-D,L):
  • Ri and R 2 are each independently C3 ⁇ 4, C 2 H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl, heterocyclic aromatic or heterocycloalkyl radical, and in addition R2 can be
  • R 3 , R4, R5, R , R 7 and 3 ⁇ 4 are each independently H, CH 3 , C2H 5 , linear alkyl or alkenyl having from 1 to 10 carbon atoms, branched or cyclic alkyl or alkenyl having from 3 to 10 carbon atoms, phenyl, substituted phenyl or heterocyclic aromatic or heterocycloalkyl radical;
  • n is independently an integer of from 1 to 5, and in addition n can be 0;
  • Preferred embodiments of formulas (IX-L), (IX-D) and (IX-D1L) include compounds of formulas (IX-L), (IX-D) and (IX-D,L) wherein:
  • R[ is H and R 2 is methyl or Ri and R 2 are methyl
  • Ri is H, R 2 is methyl, R 5 , R 6 , R 7 and R 8 are each H; I and m are each 1 ; n is 0, Ri and R 2 are methyl; R 5 , R 6 , R 7 and R 8 are each H; I and m are 1 ; n is 0.
  • the cytotoxic agent is represented by formula (IX-L).
  • Another conjugate of the present invention may be in the form of one that comprises the anti-CD 19 antibody or a homologue or fragment thereof, conjugated to a maytansinoid of formula (X):
  • is H
  • R 2 is methyl
  • R 5 , Re, R ? and Rg are each H
  • I and m are each 1
  • n is 0.
  • Rj and R 2 are methyl
  • R 5 , R 6 , R 7 , Rg are each H
  • I and m are 1
  • n is 0
  • the L-aminoacyl stereoisomer is preferred.
  • Maytansinoids may also be linked to cell binding agents using PEG linking groups, as set forth in U.S. Application No. 10/024,290. These PEG linking groups are soluble both in water and in non-aqueous solvents, and can be used to join one or more cytotoxic agents to a cell binding agent.
  • Exemplary PEG linking groups include hetero-bifunctional PEG linkers that bind to cytotoxic agents and cell binding agents at opposite ends of the linkers through a functional sulfhydryl or disulfide group at one end, and an active ester at the other end.
  • a cytotoxic conjugate using a PEG linking group reference is again made to U.S. Application No. 10/024,290 for specific details.
  • Synthesis begins with the reaction of one or more cytotoxic agents bearing a reactive
  • a cytotoxic conjugate comprising one or more cytotoxic agents covalently bonded to a cell binding agent through a PEG linking group.
  • SAR3419 an anti-CD 19 humanized monoclonal antibody (HuB4) conjugated to DM4 5 and show that it is effective as a single agent over a wide range of doses against CD 19+ BCP-ALL and MLL xenografts.
  • HuB4 humanized monoclonal antibody
  • SAR3419 is a highly effective novel therapeutic agent for ALL and its incorporation into remission induction protocols may improve the outcome for high-risk pediatric and adult CD 19+ ALL patients.
  • mice All experimental studies were approved by the Animal Care and Ethics Committee of the University of New South Wales. The establishment and characterization of a pediatric patient- derived ALL xenograft panel in NQD/SCID (NOD.CB17-PrM/cid/J) mice has been previously described ' (details can also be obtained from http://pptp.nchresearch.org/documents .html) and that of a MLL xenograft panel will be published elsewhere. Mice obtained from the Australian BioResources (Moss Vale, NSW, Australia) were inoculated intravenously with 2.5 - 5 x 10 6 ALL or MLL xenograft cells purified from spleens of previously engrafted mice.
  • All drugs were administered by intraperitoneal injection (i.p.). Unless otherwise specified drug schedules were as follows: SAR3419 1-10 mg/kg and huB4 10 mg/kg (provided by Sanofi, France, through the Cancer Therapy Evaluation Program, NCI) once a week for 3 weeks; VCR (Baxter, NSW, Australia) 0.15 mg/kg once a week for 2 weeks; DEX (Sigma- Aldrich, Australia) 5 mg kg, and L-ASNase (Leunase®, Sanofi-Aventis, Australia) 1000 U/kg, Monday to Friday for 2 weeks.
  • Example 2 Determination of in vivo response An in-depth description of the analysis methods is included in Example 2. Briefly, ALL xenograft responses to drug treatments were assessed using two activity measures, leukemia growth delay (LGD) and objective response measure (ORM) as previously described 8 . Event- free survival (EFS) was calculated for each mouse as the number of days from treatment initiation until the %huCD45+ cells in the PB reached 25%, or until mice reached a humane end- point with evidence of leukemia-related morbidity. EFS values for the different treatments were compared by Kaplan-Meier survival curves and logrank test. The LGD was calculated for each group as the difference in median EFS between treated and control mice.
  • LGD leukemia growth delay
  • ORM objective response measure
  • Each mouse was assigned an ORM score from 0 (progressive disease type 1, PD1) to 10 (maintained complete response, MCR), depending on its response profile 9 from which an overall response for the cohort was determined as the median ORM.
  • progressive disease as a continuous increase in %huCD45+ in the PB that reached event
  • stable disease as %huCD45+ in the PB that did not decrease below 1% and did not reach event
  • partial response PR
  • complete response CR when the %huCD45+ in the PB remained under 1% for two consecutive measures
  • MCR when the %huCD45+ in the PB stayed under 1% for the last three weeks of the monitoring period.
  • PD was further subdivided into the classifications PDl or PD2 based on whether the EFS of the treated, mouse was ⁇ 1.5- or > 1.5-fold, respectively, that of median EFS of the control group.
  • Median ORMs of PR, CR and MCR were considered to be Objective Responses.
  • This prophylaxis consisted of either acetaminophen 10 (100 mg/kg, Bristol-Myers Squibb, Victoria, Australia) and promethazine 11 (4 mg/kg, Hospira, Australia), or acetaminophen and CV-6209 12 (5 mg/kg, Takeda Chemical Industries, Osaka, Japan) in a 0.2 M NaCl/ 4 mg/mL glucose solution, i.p.
  • Tissues were fixed in buffered formalin, dehydrated, cleared and paraffin embedded as per standard protocols. Sections (5 ⁇ ) were re-hydrated and stained with hematoxylin and eosin (H&E) and images obtained with a microscope and digital camera.
  • H&E hematoxylin and eosin
  • SAR3419 is highly effective as a single agent against CD] 9+ ALL and MLL xenografts in vivo
  • the efficacy of SAR3419 as a single agent was first examined against a panel of 10 (7 ALL and 3 MLL) xenografts in vivo. Treatments consisted of 3 injections administered once a week i.p. at a dose of 10 mg/kg. Compared to vehicle controls, SAR3419 significantly prolonged EFS of the 8 BCP-ALLs and MLLs that express cell surface CD 19 ( Figure 1A-C and E; Figure 2, Figure 8 and Supplementary Figure S1A-B). For these xenografts the LGD ranged from 16.8 days for ALL-2 to 36.8 days for ALL-4 ( Figure 2A).
  • SAR3419 was ineffective in significantly delaying the progression of the 2 T-ALL xenografts ( Figure I D; Figure 2 and Supplementary Figure SIC), which lack CD 19 expression.
  • SAR3419 elicited Objective Responses in all MLL (1 PR, 2 CRs) and 4/5 BCP-ALL (1 PR, 3 CRs) xenografts ( Figure 2A and C).
  • ALL-3 one of the most chemosensitive BCP-ALL xenografts in the panel (ALL-3) only recorded a PD2, and both T-ALL xenografts showed PD (1 PDl, 1 PD2).
  • Xenograft responses to SAR3419 are also summarized in a "COMPARE-like" plot ( Figure 2B).
  • Figure 2B A complete summary of results is provided in Supplementary Table SI , including total numbers of mice, number of mice that died (or were otherwise excluded), numbers of mice with events and average times to events, LGD values, as well as numbers of responses and T/C values.
  • ALL- 17 One BCP-ALL xenograft (ALL- 17) was excluded from analysis due to toxicity; of the remaining 5 mice in the ALL- 17 SAR3419-treated cohort 3 achieved CR, 1 PR and 1 PDl (Supplementary Figure SI B).
  • the xenograft MLL-14 was not evaluable in terms of ORM since due to its engraftment kinetics treatments commenced before the median leukemia load in PB was over 1 % (Supplementary Figure SIC).
  • SAR3419 exerts single-agent efficacy over a wide range of doses
  • NOD/SCID mice consisting of a VXL backbone. Mice engrafted with ALL-4 and ALL-19 were treated with VXL for two weeks to induce a remission, followed immediately by either one 3- week cycle of SAR3419 treatment or continuous weekly SAR3419. VXL alone significantly delayed the progression of both xenografts, by 18.0 days for ALL-4 ( Figures 5A and 6A) and by
  • mice treated with a single 3- week cycle of SAR3419 post VXL eventually reached events as defined a priori to occur at 25% huCD45+ in the PB.
  • These mice also exhibited high leukemic infiltration of all major organs (Figure 6C).
  • the extent of leukemic infiltration was confirmed by histological examination where, compared to non-engrafted mice ( Figure 7 A), mice at leukemic relapse showed extensive infiltration of leukemia cells in spleen, liver, kidney, brain and bone marrow ( Figure 7B).
  • mice receiving the extended SAR3419 treatment did not show signs of relapse in PB ( Figure 5).
  • a cohort of mice engrafted with ALL-4 and ALL- 19 also received continuous SAR3419 treatment for at least 10 weeks post VXL induction therapy. This continuous treatment also dramatically extended the disease remission induced by VXL alone ( Figures 5A and 6). All mice in the extended treatment cohorts became morbid and were euthanized with undetectable levels of huCD45+ cells in the PB ( Figure 6). Examination of tissues at necropsy revealed negligible leukemic infiltration of all major organs except for the brain and spinal fluid, as assessed by flow cytometry (Figure 6C) and histology/immunhistochemistry (Figure 7C).
  • ALL Acute Lymphoblastic Leukemia
  • mice individual mice were categorized as PD if their percentage of hCD45 cells never dropped below 1% and they had an event before the end of the study period.
  • An event is defined as hCD45 cells above 25% in the peripheral blood with times to event calculated as above.
  • Individual mice were classified as SD if their percentage of hCD45 cells never dropped below 1% and no event occurred before the end of the study.
  • PR was assigned if the percentage of cells dropped below 1% for any one time point regardless of whether the percentage eventually reached 25%.
  • a CR was assigned if the percentage of hCD45 cells dropped below 1% for 2 consecutive weeks of the study and regardless of whether the percentage reached 25% or not.
  • a CR was considered maintained if the percentage of hCD45 was less than 1% for the last three measurements of the study.
  • PD was further classified into PD1 and PD2 according to the TGD value. Summary statistics and analysis methods
  • EFS T/C value An EFS T/C value was defined by the ratio of the median time to event of the treatment group and the median time to event of the respective control group. If the treatment group did not have a median time to event, then EFS T/C was defined as greater than the ratio of the last day of the study for the treatment group divided by the median time to event for the control group.
  • agents are considered highly active if they meet three criteria: a) an EFS T/C > 2; b) a significant difference in EFS distributions (p ⁇ 0.050), and c) a net reduction in median tumor volume for animals in the treated group at the end of treatment as compared to at treatment initiation.
  • Agents meeting the first two criteria, but not having a net reduction in median tumor volume for treated animals at the end of the study are considered to have intermediate activity.
  • Agents with an EFS T/C ⁇ 2 are considered to have low levels of activity.
  • Xenografts in which the median EFS for the control line was greater than one- half of the study period or in which the median EFS for the control line did not exist are considered not evaluable for the EFS T/C measure of activity.
  • ALL-3 69 (66-71) 58 (49-59) 30 (29-31)
  • T-ALL ALL- 16 0.7 (0.6-0.8) 0.75 (0.7-0.8) 1.4 (0.7-2.1)
  • Figure SI Single agent efficacy of SAR3419.
  • NOD/SCID mice engrafted with ALL-16 (A); ALL-17 (B); or MLL-14 (C) were treated with vehicle (dashed lines) or 10 mg/kg SAR3419 (solid lines) once a week for 3 weeks.
  • the response to treatment was monitored by weekly measurements of the %huCD45 + cells in PB of individual mice (left panel).
  • the EFS time to reach 25% of leukemia cells in PB is represented by Kaplan-Meier plots (right panel). Gray arrows indicate treatment time points.
  • SAR3419 is effective against BCP-ALL xenografts in vivo over a broad dose range.
  • Mice engrafted with ALL-4 (A) were treated with vehicle control (dotted black line), or SAR3419 at 10 mg/kg (solid red line), 7.5 mg/kg (solid geen line), 5 mg/kg (solid blue line), 2.5 mg/kg (solid orange line) or with the unconjugated MAb huB4 (gray dotted line) while mice engrafted with ALL- 19 (B) were treated with vehicle control (dotted black line), or SAR3419 at 10 mg/kg (solid red line) and at 1.0 mg/kg (solid blue line).
  • Response to treatment was monitored by weekly enumeration of the proportion of %huCD45 + cells in the PB of individual mice (left panels), and Kaplan-Meier analysis of EFS (right panels). Gray arrows indicate treatment time points.
  • FIG. 1 Histological confirmation of leukemic infiltrates of murine tissues at necropsy. H&E staining of tissues collected from (A) non-engrafted mouse; or mice engrafted with ALL- 19 and treated with: (B) VXL/SAR3419 x 3 or (C) VXL/SAR3419 extended treatment.
  • BM bone marrow Spl, spleen; Br: brain. The gray solid bar in the low left corner indicates size (200 micrometers).
  • Table 2 Relative fluorescence intensity of CD19 surface expression on xenograft cells from spleen, bone marrow or peripheral

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Abstract

L'invention concerne un procédé de traitement d'un individu ayant une maladie caractérisée par la présence de cellules CD19 positives néoplasiques, lequel procédé comprend l'utilisation de conjugués anticorps médicament.
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WO2009052431A2 (fr) * 2007-10-19 2009-04-23 Seattle Genetics, Inc. Agents de liaison au cd19 et utilisations de ceux-ci

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WO2009052431A2 (fr) * 2007-10-19 2009-04-23 Seattle Genetics, Inc. Agents de liaison au cd19 et utilisations de ceux-ci

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BLANC, V. ET AL.: "SAR3419: An Anti-CD19-Maytansinoid Immunoconjugate for the Treatment of B-Cell Malignancies", CLINICAL CANCER RESEARCH, vol. 17, no. 20, 14 October 2011 (2011-10-14), pages 6448 - 6458, XP055012063 *
COIFFIER, B. ET AL.: "Phase I/II study of the anti-CD19 maytansinoid immunoconjugate SAR3419 administered weekly to patients (pts) with relapsed/refractory B-Cell non-Hodgkin lymphoma (NHL)", JOURNAL OF CLINICAL ONCOLOGY, vol. 29, no. 15, 20 May 2011 (2011-05-20) *

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