DOCSLIB.ORG

Novel Drugs in the Pipeline

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Novel Drugs in the Pipeline Institute of Biomedical University of Salamanca Cancer Research Center Research of Salamanca Novel Drugs in the pipeline Enrique M. Ocio University Hospital & Cancer Research Center University of Salamanca Spain Disclosures Type Company Amgen; Celgene; Novartis; BMS, Janssen, Honoraria Takeda Celgene; Amgen; Novartis, Takeda, Abbvie, Consultancy Pharmamar, Seattle Genetics Array Pharmaceuticals; Mundipharma; Celgene; Research Funding Amgen, Sanofi, MSD Treatment of MM 1844 1960 1970 1980 1990 2000 2003 2004 2013 2015 2018 Mr. Melphalan McBean (1958, Blokhin) HD chemo 1844 Ann NY Acad Sci ASCT Bortezomib Lenalidomide Melphalan Glucocorticoids Thalidomide Panobinostat (1969) Daratumumab Elotuzumab Ixazomib Combination chemo Vincristine Doxorubicin Carfilzomib Dexamethasone Pomalidomide Chemotherapy Era Targeted Therapy Era Do we need other agents with novel MoA? New drugs and mechanisms of action in MM CS-1 Elotuzumab CDK 1, 2, 5, 9 Dinaciclib / TG02 CD38 Daratumumab / Isatuximab FGFR3 Dovitinib / AB1010 / MFGR 1877S CD138 nBT062-DM4 cKit /PDGFR Imatinib / Dasatinib MoAb CD56 Lorvotuzumab VEGF-R Bevacizumab CD40 Dacetuzumab / Lucatumumab IGF-1R AVE1642 / CP-751, 851 BAFF Tabalumab Kinase Inh. EGF-R Cetuximab KiR IPH2101 PKC Enzastaurin PD1/PDL1 Pembrolizumab / Nivolumab / Pidilumab BTK Ibrutinib IL-6 Siltuximab Cell cycle Inh. Lymph. Ras NK cell KSP Inh Filanesib Aurora K Inh MLN8237 Raf PI3K CDK 4/6 Inh Seleciclib IMIDs MEK Akt Thalidomide Lenalidomide Alkylators Pomalidomide mTORC1 mTORC2 Melphalan Cyclophosphamide MAPK Bendamustine Melflufen Signaling Pathways TH-302 AKT Perifosine / Afuresertib mTORC1 Everolimus / Temsirolimus mTOR C1/C2 MLN0128 / INK128 Other DNA damaging Farn Transf Tipifarnib Proteasome Inh. p38/MAPK inh SCIO-469 DNA Damaging Zalypsis DACi p38/JNK act Aplidin Bortezomib MEK Selumetinib PARP Inhibitor Veliparib Panobinostat Carfilzomib Hsp-90 Inh. Bcl-2 Venetoclax Vorinostat Ixazomib XPO Selinexor Tanespimycin Romidepsin Oprozomib PIM PIM447 AUY922 Givinostat Marizomib Rocilinostat Approved Ocio, Leukemia 2014. Updated Are there alternative alkylators or should we forget them for the future? Melflufen: clever alkylator Melflufen is a peptidase enhanced therapy with an alkylating payload 1. Amino- peptidases highly Peptidase potentiated activity in over expressed in 5. Melflufen and MM cells results in: multiple myeloma hydrophilic (MM) cells alkylating • Approx. 50-fold higher intra- 1,5 moieties binds cellular exposure in MM cells directly to DNA • Approx. 50-fold higher anti-MM potency1,2,5 • Alkylation of DNA with limited or no induction of DNA repair3,5 • Strong anti-angiogenic properties 1,4,5 • Therapeutic index of 20 - 40 (MM cells compared with peripheral 2. Lipophilic blood mononuclear cells)1,5 melflufen rapidly traverses cell membranes Melflufen Amino-peptidase Alkylating moiety 3. Amino-peptidase potentiated release of 1. Chauhan et al. (2013) Clin Cancer Res 19(11): 3019-303. hydrophilic alkylating 4. Hydrophilic moieties alkylating 2. Wickstrom et al. (2008) Invest New Drugs 26(3): 195-204. moieties trapped 3. Ray et al. (2016) Br J Hematol 174: 397-409 inside the cell 4. Strese et al. (2013) Biochem Pharmacol 86: 888–895. 5. Wickström et al. (2017) Oncotarget E-pub June 08. Melflufen + Dex Phase II O-12-M1 trial PFS 5.7 m (95% CI: 3.7-9.3) RRMM pts ≥ 2 prior lines including Len and Btz and refr. to last line. n=45 4 (2-14) prior lines; 64% double refr.; 53% Alkylator refr. ORR 41% .......... 5 VGPR & 9 PR 36% in Alkylator refr. G3/4 rel. TEAEs: Thromboc. (58%), Neutropenia (51%), Anemia: 42% DOR for ≥ PR: 8.4 m Richardson P. ASH 2017 Phase II Horizon trial * RRMM pts ≥ 2 prior lines including IMiD & PI and refr to Pom and/or Dara n=38 6 (3-11) prior lines; Alkylator refr. 57% Pom refr; 96%; Pom & Dara Refr: 62% ORR 27% .......... 2 VGPR & 6 PR G3/4 rel. TEAEs: Thromboc. (45%), Neutropenia (39%), Anemia: 21% * 11 prior lines including Allo-SCT Mateos MV. ASH 2017 Melflufen 40 mg iv every 28 days + Dex 40 mg weekly Melflufen ongoing studies in RR MM Phase 2 Phase 3 Phase 1/2 – Triple combination Single Arm Multi-refr. study Randomized study study How does melflufen work in How does melflufen compare to QUESTION How is melflufen dosed in triple RRMM patients with limited standard of care in late-stage ASKED combinations in RRMM? treatment options? RRMM? Recruitment ongoing Recruitment ongoing Recruitment ongoing COMMENT Combination with bortezomib or Pomalidomide- and/or H2H melflufen vs pomalidomide daratumumab-refractory patients daratumumab EDO-S101: bendamustine derivative (tinostamustine) Bendamustine Purine-like HDAC Benzimidazole ring HDAC DAC Inhibitor Alkylator HDAC Ac Ac Butyric acid group DNA Alkylation Moiety Ac Ac Ac EDO-S101 Purine-like Benzimidazole ring DACi Moiety DNA Alkylation Moiety EDO-S101 induces potent DNA Damage Response EDO-S101 Induces DSBs Control MM1S EDO-S101 5 μM EDO-S101 activates sensors of DNA damage EDO-S101 5 µM (hours) 0 12 24 48 pATR - 300 pCHK1 -56 pATM - 350 Bendamustine EDO-S101 MW C12.55 C12.5525 pCHK2 -62 (Kd) P-CHK1 -56 -53 pP53 P-CHK2 -62 pH2AX pH2AX -17 -17 Ac-H3 -17 Tubulin -55 Lopez Iglesias et al, J. Hematol Oncol 2017 In vivo activity of EDO-S101 Small tumors Big tumors 6000 Treatment period 350 Control EDO-S101 5000 300 ) 3 Treatment period 250 Control EDO-S101 4000 200 150 3000 Tumor volume (%) 100 2000 50 Tumor volume (mm 0 1000 1 8 19 31 43 Time in days 0 0 102030405060708090 Time in days Vk12653 model 1,0 0,8 EDO-S101 is the only drug 0,6 with single agent activity in the Vk12653 model, where is 0,4 also able to prolong survival 0,2 Cumulative survival 0,0 0 20 40 60 80 100 Time in days Lopez Iglesias et al, J. Hematol Oncol 2017 Which other pathogenetic features can be targeted in MM? Is there any Bcr/Abl or t(15;17) in MM? Cyclin D dereg. an early and common event Bergsagel. Blood 2005 Filanesib (KSP inh.) in MM Kinesin spindle protein is required for cell cycle progression • ARRY-520 induces mytotic arrest and subsequent apoptosis • Particularly effective in Mcl-1 dependent cells • Efficacy inversely correlates with serum AAG levels ARRY-520 + G-CSF ………………………....................… ≥ PR 16%; ≥ MR 19% n= 32 exp. to BTZ & IMID. Median lines 6 (2-19) ARRY-520 + G-CSF + Dex……………………..…….….. ≥ PR 16%; ≥ MR 22% n= 50 refr. to BTZ, Len, Dex. Median lines 9 (5-13) Gr 3/4 AEs: neutropenia (38%, 38%), thromboc. (44%, 42%), anemia (38%, 50%), fatigue (16%,8%), leukop. (13%, 4%) Lonial S. ASH 2013. Abstract 285 Rationale for this combination Inhibition of KSP in MM1S cells (% of monopolar spindles) Control In vivo activity of PDF Bipolar spindles 14% Bipolar spindles Bipolar spindles Filanesib 10 nM x 24 h 97% Monopolar spindles Hernández-García S. Haematologica 2017 Phase I/II Pomdefil: Pom-Dex + Filanesib in RRMM n= 44 3 (2-6) prior lines & 76% double refr. Influence of baseline AAG levels Alpha-1-Acid Glycoprotein ORR 60% … (1 CR; 4 VGPR, 13 PR) Median level was 85.5 mg/dL (50.6-179.9) • No pt. with AAG values over the median 1.0 PFS responded (1 SD and 4 PD) 0.8 • All 6 pts with AAG below the median 0.6 achieved ≥MR (1 VGPR, 3 PR and 2 MR) 0.4 PFS according to AAG levels 0.2 Cum. Survival 7 m (4.1 - 9.9) 1.0 0.0 0 5 10 15 20 25 0.8 Months 0.6 Low (below median) High (above median) 0.4 OS 24 m (9.8 - 38.1) Cum. Survival 0.2 0.0 Main toxicity was hematological: 0 2 4 6 8 10 12 G3/4 Tx related Neutrop. (56%); Thrombocytop. (17%) & Anemia (25%) Months Median follow-up of 8 months (0-27) Ocio et al. ASH 2017 RAS family members are the most frequently mutated genes in MM 41 oncogenes and tumor suppressor genes were Massively parallel sequencing of 38 tumor genomes tested using MassARRAY/Sequenom mass and their comparison to matched normal DNAs spectrometry–based methodology in 133 RRMM. Chapman et al. Nature 2011 Mulligan et al. Blood 2014 23% 24% 26% 20% 2% Massively parallel 23% 20% sequencing of paired tumor/normal samples from 6% 203 multiple myeloma (MM) Lohr et al. Cancer Cell 2014 New drugs and mechanisms of action in MM Lymph. Ras NK cell Raf PI3K MEK Akt mTORC1 mTORC2 MAPK Signaling Pathways AKT Perifosine / Afuresertib mTORC1 Everolimus / Temsirolimus mTOR C1/C2 MLN0128 / INK128 Farn Transf Tipifarnib p38/MAPK inh SCIO-469 p38/JNK act Aplidin MEK Selumetinib Bcl-2 Venetoclax XPO Selinexor PIM PIM447 Approved Ocio, Leukemia 2014. Updated Venetoclax (Bcl-2 inhibitor) • Venetoclax (ABT-199 / GDC-0199) is a potent, selective, orally bioavailable, small- molecule, BCL-2 inhibitor1 • Anti-apoptotic proteins BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival2 • Venetoclax induces cell death in multiple myeloma (MM) cell lines and primary samples, particularly those positive for the translocation t(11;14),which correlates with higher ratios of BCL2 to MCL1 and BCL2 to 2,3 BCL2L1 (BCL-XL) mRNA 2. Touzeau C, et al. Leukemia. 2014; 28(1): 210-212. 1. Souers AJ, et al. Nat Med. 2013; 19(2): 202-208. 3. Punnoose E et al. Mol Cancer Ther 2016 Venetoclax monotherapy n= 66 pts. 5 prior lines (1-15). 79% refr. to last line; 61% double refractory to Btz & Len. t(11;14): 46% Time to Progression 100% t(11;14) 6.6 (3.9-10.2) Non t(11;14) 1.9 (1.2-2.3) 88% in t(11;14) with a high BCL2:BCL2L1 ratio Main toxicities are mild GI symptoms; thrombocytopenia (32% G3-4) and neutropenia (27% G3-4) 30-1200 mg po (MTD: 1200 mg) Kumar, et al.
Load more

Recommended publications
  • Predictive QSAR Tools to Aid in Early Process Development of Monoclonal Antibodies
    Predictive QSAR tools to aid in early process development of monoclonal antibodies John Micael Andreas Karlberg Published work submitted to Newcastle University for the degree of Doctor of Philosophy in the School of Engineering November 2019 Abstract Monoclonal antibodies (mAbs) have become one of the fastest growing markets for diagnostic and therapeutic treatments over the last 30 years with a global sales revenue around $89 billion reported in 2017. A popular framework widely used in pharmaceutical industries for designing manufacturing processes for mAbs is Quality by Design (QbD) due to providing a structured and systematic approach in investigation and screening process parameters that might influence the product quality. However, due to the large number of product quality attributes (CQAs) and process parameters that exist in an mAb process platform, extensive investigation is needed to characterise their impact on the product quality which makes the process development costly and time consuming. There is thus an urgent need for methods and tools that can be used for early risk-based selection of critical product properties and process factors to reduce the number of potential factors that have to be investigated, thereby aiding in speeding up the process development and reduce costs. In this study, a framework for predictive model development based on Quantitative Structure- Activity Relationship (QSAR) modelling was developed to link structural features and properties of mAbs to Hydrophobic Interaction Chromatography (HIC) retention times and expressed mAb yield from HEK cells. Model development was based on a structured approach for incremental model refinement and evaluation that aided in increasing model performance until becoming acceptable in accordance to the OECD guidelines for QSAR models.
    [Show full text]
  • Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix
    United States International Trade Commission Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix USITC Publication 4208 December 2010 U.S. International Trade Commission COMMISSIONERS Deanna Tanner Okun, Chairman Irving A. Williamson, Vice Chairman Charlotte R. Lane Daniel R. Pearson Shara L. Aranoff Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix Publication 4208 December 2010 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 15, 2010, set forth at the end of this publication, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the United States International Trade Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement changes to the Pharmaceutical Appendix, effective on January 1, 2011. Table 1 International Nonproprietary Name (INN) products proposed for addition to the Pharmaceutical Appendix to the Harmonized Tariff Schedule INN CAS Number Abagovomab 792921-10-9 Aclidinium Bromide 320345-99-1 Aderbasib 791828-58-5 Adipiplon 840486-93-3 Adoprazine 222551-17-9 Afimoxifene 68392-35-8 Aflibercept 862111-32-8 Agatolimod
    [Show full text]
  • New Biological Therapies: Introduction to the Basis of the Risk of Infection
    New biological therapies: introduction to the basis of the risk of infection Mario FERNÁNDEZ RUIZ, MD, PhD Unit of Infectious Diseases Hospital Universitario “12 de Octubre”, Madrid ESCMIDInstituto de Investigación eLibraryHospital “12 de Octubre” (i+12) © by author Transparency Declaration Over the last 24 months I have received honoraria for talks on behalf of • Astellas Pharma • Gillead Sciences • Roche • Sanofi • Qiagen Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Paul Ehrlich (1854-1915) • “side-chain” theory (1897) • receptor-ligand concept (1900) • “magic bullet” theory • foundation for specific chemotherapy (1906) • Nobel Prize in Physiology and Medicine (1908) (together with Metchnikoff) Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author 1981: B-1 antibody (tositumomab) anti-CD20 monoclonal antibody 1997: FDA approval of rituximab for the treatment of relapsed or refractory CD20-positive NHL 2001: FDA approval of imatinib for the treatment of chronic myelogenous leukemia Infections and biologicals: a real concern? (two-hour symposium): New biological therapies: introduction to the ESCMIDbasis of the risk of infection eLibrary © by author Functional classification of targeted (biological) agents • Agents targeting soluble immune effector molecules • Agents targeting cell surface receptors
    [Show full text]
  • B-Cell Targets to Treat Antibody-Mediated Rejection In
    Muro et al. Int J Transplant Res Med 2016, 2:023 Volume 2 | Issue 2 International Journal of Transplantation Research and Medicine Commentary: Open Access B-Cell Targets to Treat Antibody-Mediated Rejection in Transplantation Manuel Muro1*, Santiago Llorente2, Jose A Galian1, Francisco Boix1, Jorge Eguia1, Gema Gonzalez-Martinez1, Maria R Moya-Quiles1 and Alfredo Minguela1 1Immunology Service, University Clinic Hospital Virgen de la Arrixaca, Spain 2Nephrology Service, University Clinic Hospital Virgen de la Arrixaca, Spain *Corresponding author: Manuel Muro, PhD, Immunology Service, University Clinic Hospital “Virgen de la Arrixaca”, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain, Tel: 34-968-369599, E-mail: [email protected] Antibody-mediated rejection (AMR) in allograft transplantation APRIL (a proliferation-inducing ligand). These co-activation signals can be defined with a rapid increase in the levels of specific are required for B-cell differentiation into plasma cell and enhancing serological parameters after organ transplantation, presence of donor their posterior survival and are a key determinant of whether specific antibodies (DSAs) against human leukocyte antigen (HLA) developing B-cells will survive or die during the establishment molecules, blood group (ABO) antigens and/or endothelial cell of immuno-tolerance [5,6]. Important used agents commercially antigens (e.g. MICA, ECA, Vimentin, or ETAR) and also particular available are Tocilizumab (anti-IL6R) and Belimumab (BAFF). histological parameters [1,2]. If the AMR persists or progresses, the The receptors of BAFF and APRIL could also be important as treatment to eliminate the humoral component of acute rejection eventual targets, for example BAFF-R, TACI (transmembrane include three sequential steps: (a) steroid pulses, antibody removal activator and calcium modulator and cyclophyllin ligand interactor) (plasma exchange or immuno-adsorption) and high doses of and BCMA (B-cell maturation antigen).
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9,161,992 B2 Jefferies Et Al
    US009 161992B2 (12) United States Patent (10) Patent No.: US 9,161,992 B2 Jefferies et al. (45) Date of Patent: Oct. 20, 2015 (54) P97 FRAGMENTS WITH TRANSFER 4,683.202 A 7, 1987 Mullis ACTIVITY 4,704,362 A 11/1987 Itakura et al. 4,766,075 A 8, 1988 Goeddeletal. (71) Applicant: biosis Technologies, Inc., Richmond 4,800,1594,784.950 A 11/19881/1989 MullisHagen et al. (CA) 4,801,542 A 1/1989 Murray et al. 4.866,042 A 9, 1989 Neuwelt (72) Inventors: Wilfred Jefferies, South Surrey (CA); 4,935,349 A 6/1990 McKnight et al. Mei Mei Tian, Coquitlam (CA): 4.946,778 A 8, 1990 Ladner et al. Timothy Vitalis, Vancouver (CA) 5,091,513 A 2f1992 Huston et al. 5,132,405 A 7, 1992 Huston et al. (73) Assignee: biOasis Technologies, Inc., British 5, 186,941 A 2f1993 Callahan et al. Columbia (CA) 5,672,683 A 9, 1997 Friden et al. 5,677,171 A 10, 1997 Hudziak et al. c - r 5,720,937 A 2f1998 Hudziak et al. (*) Notice: Subject to any disclaimer, the term of this 5,720,954. A 2f1998 Hudziak et al. patent is extended or adjusted under 35 5,725,856 A 3, 1998 Hudziak et al. U.S.C. 154(b) by 0 days. 5,770,195 A 6/1998 Hudziak et al. 5,772,997 A 6/1998 Hudziak et al. (21) Appl. No.: 14/226,506 5,844,093 A 12/1998 Kettleborough et al. 5,962,012 A 10, 1999 Lin et al.
    [Show full text]
  • Monoclonal Antibodies in Myeloma
    Monoclonal Antibodies in Myeloma Pia Sondergeld, PhD, Niels W. C. J. van de Donk, MD, PhD, Paul G. Richardson, MD, and Torben Plesner, MD Dr Sondergeld is a medical student at the Abstract: The development of monoclonal antibodies (mAbs) for University of Giessen in Giessen, Germany. the treatment of disease goes back to the vision of Paul Ehrlich in Dr van de Donk is a hematologist in the the late 19th century; however, the first successful treatment with department of hematology at the VU a mAb was not until 1982, in a lymphoma patient. In multiple University Medical Center in Amsterdam, The Netherlands. Dr Richardson is the R.J. myeloma, mAbs are a very recent and exciting addition to the Corman Professor of Medicine at Harvard therapeutic armamentarium. The incorporation of mAbs into Medical School, and clinical program current treatment strategies is hoped to enable more effective and leader and director of clinical research targeted treatment, resulting in improved outcomes for patients. at the Jerome Lipper Myeloma Center, A number of targets have been identified, including molecules division of hematologic malignancy, depart- on the surface of the myeloma cell and components of the bone ment of medical oncology, Dana-Farber Cancer Institute in Boston, MA. Dr Plesner marrow microenvironment. Our review focuses on a small number is a professor of hematology at the Univer- of promising mAbs directed against molecules on the surface of sity of Southern Denmark and a consultant myeloma cells, including CS1 (elotuzumab), CD38 (daratumumab, in the department of hematology at Vejle SAR650984, MOR03087), CD56 (lorvotuzumab mertansine), and Hospital in Vejle, Denmark.
    [Show full text]
  • The Two Tontti Tudiul Lui Hi Ha Unit
    THETWO TONTTI USTUDIUL 20170267753A1 LUI HI HA UNIT ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2017 /0267753 A1 Ehrenpreis (43 ) Pub . Date : Sep . 21 , 2017 ( 54 ) COMBINATION THERAPY FOR (52 ) U .S . CI. CO - ADMINISTRATION OF MONOCLONAL CPC .. .. CO7K 16 / 241 ( 2013 .01 ) ; A61K 39 / 3955 ANTIBODIES ( 2013 .01 ) ; A61K 31 /4706 ( 2013 .01 ) ; A61K 31 / 165 ( 2013 .01 ) ; CO7K 2317 /21 (2013 . 01 ) ; (71 ) Applicant: Eli D Ehrenpreis , Skokie , IL (US ) CO7K 2317/ 24 ( 2013. 01 ) ; A61K 2039/ 505 ( 2013 .01 ) (72 ) Inventor : Eli D Ehrenpreis, Skokie , IL (US ) (57 ) ABSTRACT Disclosed are methods for enhancing the efficacy of mono (21 ) Appl. No. : 15 /605 ,212 clonal antibody therapy , which entails co - administering a therapeutic monoclonal antibody , or a functional fragment (22 ) Filed : May 25 , 2017 thereof, and an effective amount of colchicine or hydroxy chloroquine , or a combination thereof, to a patient in need Related U . S . Application Data thereof . Also disclosed are methods of prolonging or increasing the time a monoclonal antibody remains in the (63 ) Continuation - in - part of application No . 14 / 947 , 193 , circulation of a patient, which entails co - administering a filed on Nov. 20 , 2015 . therapeutic monoclonal antibody , or a functional fragment ( 60 ) Provisional application No . 62/ 082, 682 , filed on Nov . of the monoclonal antibody , and an effective amount of 21 , 2014 . colchicine or hydroxychloroquine , or a combination thereof, to a patient in need thereof, wherein the time themonoclonal antibody remains in the circulation ( e . g . , blood serum ) of the Publication Classification patient is increased relative to the same regimen of admin (51 ) Int .
    [Show full text]
  • Monoclonal Antibody-Based Therapy As a New Treatment Strategy in Multiple Myeloma
    Leukemia (2012) 26, 199–213 & 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12 www.nature.com/leu REVIEW Monoclonal antibody-based therapy as a new treatment strategy in multiple myeloma NWCJ van de Donk1, S Kamps1, T Mutis2 and HM Lokhorst1 1Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands and 2Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands The introduction of autologous stem cell transplantation the myeloma patients achieved a partial response (PR) or stable combined with the introduction of immunomodulatory drugs disease following rituximab therapy. All these patients expressed (IMiDs) and proteasome inhibitors has significantly improved CD20 on their myeloma cells.2 However, as only B15–20% of survival of multiple myeloma patients. However, ultimately the majority of patients will develop refractory disease, indicating all myeloma patients express CD20 on their bone marrow the need for new treatment modalities. In preclinical and clinical plasma cells, new targets for immunotherapy need to be studies, promising results have been obtained with several identified. The search for other targets has led to the develop- monoclonal antibodies (mAbs) targeting the myeloma tumor ment of mAbs targeting growth factor receptors or adhesion cell or the bone marrow microenvironment. The mechanisms molecules on myeloma cells. Other newly developed mAbs underlying the therapeutic efficacy of these mAbs include are directed against cellular or non-cellular components of the direct induction of tumor cell apoptosis via inhibition or activation of target molecules, complement-dependent cyto- bone marrow microenvironment, resulting in the neutraliza- toxicity and antibody-dependent cell-mediated cytotoxicity tion of growth factors, inhibition of angiogenesis, modulation (ADCC).
    [Show full text]
  • Distinct Apoptotic Signaling Characteristics of the Anti-CD40
    Published OnlineFirst May 24, 2011; DOI: 10.1158/1078-0432.CCR-11-0479 Clinical Cancer Cancer Therapy: Preclinical Research Distinct Apoptotic Signaling Characteristics of the Anti-CD40 Monoclonal Antibody Dacetuzumab and Rituximab Produce Enhanced Antitumor Activity in Non-Hodgkin Lymphoma Timothy S. Lewis1, Renee S. McCormick1, Kim Emmerton1, Jeffrey T. Lau3, Shang-Fan Yu3, Julie A. McEarchern2, Iqbal S. Grewal1, and Che-Leung Law1 Abstract Purpose: Individually targeting B-cell antigens with monoclonal antibody therapeutics has improved the treatment of non-Hodgkin lymphoma (NHL). We examined if the antitumor activity of rituximab, CD20-specific antibody, could be improved by simultaneously targeting CD40 with the humanized monoclonal antibody dacetuzumab (SGN-40). Experimental Design: Dacetuzumab was dosed with rituximab to determine the in vivo activity of this combination in a subcutaneous Ramos xenograft model of non-Hodgkin lymphoma (NHL). The effect of dacetuzumab on rituximab antibody-dependent cell mediated–cytotoxicity (ADCC), antiproliferative, and apoptotic activities were evaluated in vitro using NHL cell lines. Western blotting and flow cytometry were used to contrast the signaling pathways activated by dacetuzumab and rituximab in NHL cells. Results: The dacetuzumab-rituximab combination had significantly improved antitumor activity over the equivalent dose of rituximab in the Ramos xenograft model (P ¼ 0.0021). Dacetuzumab did not augment rituximab-mediated ADCC activity; however, these antibodies were additive to synergistic in cell- proliferation assays and produced increased apoptosis in combination. Rituximab signaling downregu- lated BCL-6 oncoprotein in a cell line–specific manner, whereas dacetuzumab strongly downregulated BCL-6 in each cell line. Dacetuzumab induced expression of the proapoptotic proteins TAp63 and Fas, whereas rituximab did not affect basal expression of either protein.
    [Show full text]
  • (INN) for Biological and Biotechnological Substances
    INN Working Document 05.179 Update 2013 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) INN Working Document 05.179 Distr.: GENERAL ENGLISH ONLY 2013 International Nonproprietary Names (INN) for biological and biotechnological substances (a review) International Nonproprietary Names (INN) Programme Technologies Standards and Norms (TSN) Regulation of Medicines and other Health Technologies (RHT) Essential Medicines and Health Products (EMP) International Nonproprietary Names (INN) for biological and biotechnological substances (a review) © World Health Organization 2013 All rights reserved. Publications of the World Health Organization are available on the WHO web site (www.who.int ) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected] ). Requests for permission to reproduce or translate WHO publications – whether for sale or for non-commercial distribution – should be addressed to WHO Press through the WHO web site (http://www.who.int/about/licensing/copyright_form/en/index.html ). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned.
    [Show full text]
  • Ep 3321281 A1
    (19) TZZ¥¥ _ __T (11) EP 3 321 281 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 16.05.2018 Bulletin 2018/20 C07K 14/79 (2006.01) A61K 38/40 (2006.01) A61K 38/00 (2006.01) A61K 38/17 (2006.01) (2006.01) (2006.01) (21) Application number: 17192980.5 A61K 39/395 A61K 39/44 C07K 16/18 (2006.01) (22) Date of filing: 03.08.2012 (84) Designated Contracting States: • TIAN, Mei Mei AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Coquitlam, BC V3J 7E6 (CA) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • VITALIS, Timothy PL PT RO RS SE SI SK SM TR Vancouver, BC V6Z 2N1 (CA) (30) Priority: 05.08.2011 US 201161515792 P (74) Representative: Gowshall, Jonathan Vallance Forresters IP LLP (62) Document number(s) of the earlier application(s) in Skygarden accordance with Art. 76 EPC: Erika-Mann-Strasse 11 12746240.6 / 2 739 649 80636 München (DE) (71) Applicant: biOasis Technologies Inc Remarks: Richmond BC V6X 2W8 (CA) •This application was filed on 25.09.2017 as a divisional application to the application mentioned (72) Inventors: under INID code 62. • JEFFERIES, Wilfred •Claims filed after the date of receipt of the divisional South Surrey, BC V4A 2V5 (CA) application (Rule 68(4) EPC). (54) P97 FRAGMENTS WITH TRANSFER ACTIVITY (57) The present invention is related to fragments of duction of the melanotransferrin fragment conjugated to human melanotransferrin (p97). In particular, this inven- a therapeutic or diagnostic agent to a subject.
    [Show full text]
  • Seattle Genetics Likely to Remain Attractive
    October 08, 2009 Seattle Genetics likely to remain attractive Evaluate Vantage The 17% decline in Seattle Genetics’ share price to $10.90 in the three days since a phase IIb trial for dacetuzumab (SGN-40) in B-cell lymphoma was stopped looks overly harsh, no doubt compounded by some shareholders taking the opportunity to cash in their profits with the stock recently touching a record high of $14.80 since the company went public in 2001. Seattle’s shares gained 66% this year to their peak on September 21 which valued the company at a very impressive $1.29bn. Without an approved product and yet to take an antibody candidate into phase III tests, the driving force behind these gains is undoubtedly Seattle’s largely unpartnered antibody technology platform, an asset for which big pharma has shown an increasingly healthy appetite for in recent times (M&A spotlight on antibody companies, July 24, 2009). Setback but chances to recapture confidence The phase IIb trial of dacetuzumab had to be stopped after an interim analysis revealed that the dacetuzumab combination treatment arm was unlikely to meet its primary efficacy endpoint of superior response rate compared to a placebo combination arm. Whilst this is clearly a worrying efficacy signal for dacetuzumab, judgement on the antibody is likely to be reserved by Seattle’s partner, Roche, until the results of four ongoing phase Ib studies, in non-Hodgkin lymphoma and multiple myeloma, are revealed. In addition, dacetuzumab was the least advanced or valuable of Seattle’s three key phase II antibody
    [Show full text]