DOCSLIB.ORG

Open Full Page

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Open Full Page Published OnlineFirst December 3, 2012; DOI: 10.1158/1078-0432.CCR-12-2046 Clinical Cancer Cancer Therapy: Preclinical Research Milatuzumab-Conjugated Liposomes as Targeted Dexamethasone Carriers for Therapeutic Delivery in CD74þ B-cell Malignancies Yicheng Mao1,2, Georgia Triantafillou1, Erin Hertlein1, William Towns1, Matthew Stefanovski1, Xiaokui Mo4, David Jarjoura4, Mitch Phelps2, Guido Marcucci1, Ly James Lee5, David M. Goldenberg6, Robert J. Lee2, John C. Byrd1,3, and Natarajan Muthusamy1 Abstract Purpose: Corticosteroids are widely used for the treatment of B-cell malignancies, including non– Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia; however, this class of drug is associated with undesirable off-target effects. Herein, we developed novel milatuzumab- þ conjugated liposomes as a targeted dexamethasone carrier for therapeutic delivery in CD74 B-cell malignancies and explored its effect against the disease. þ Experimental Design: The targeting efficiency of milatuzumab-targeted liposomes to CD74 cells was evaluated in vitro. The effect of CD74-targeted liposomal dexamethasone was compared with free dexa- methasone in primary CLL cells and cell lines in vitro. The therapeutic efficacy of CD74-targeted liposomal dexamethasone was evaluated in a Raji-severe combined immunodeficient (SCID) xenograft model in vivo. Results: Milatuzumab-targeted liposomes promoted selective incorporation of carrier molecules into transformed CD74-positive B cells as compared with CD74-negative T-cells. The CD74-dexamethasone– targeted liposomes (CD74-IL-DEX) promoted and increased killing in CD74-positive tumor cells and primary CLL cells. Furthermore, the targeted drug liposomes showed enhanced therapeutic efficacy against a CD74-positive B-cell model as compared with free, or non-targeted, liposomal dexamethasone in SCID mice engrafted with Raji cells in vivo. Conclusions: These studies provide evidence and support for a potential use of CD74-targeted liposomal dexamethasone as a new therapy for B-cell malignancies. Clin Cancer Res; 19(2); 1–10. Ó2012 AACR. Introduction (CLL), include chemotherapy, antibody therapy, and corti- Treatment options for patients with B-cell malignancies, costeroids (1–4). Potent corticosteroids such as dexameth- including non–Hodgkin lymphoma (NHL), acute lympho- asone (DEX) can induce apoptosis in malignant B cells by blastic leukemia (ALL), and chronic lymphocytic leukemia numerous pathways, including caspase activation, interleu- kin regulation, upregulation of proapoptotic protein BIM, and modulation of prosurvival factors, such as Bcl-2, Bcl-xL, AP-1, and NF-kB (5–7). In addition, corticosteroids can Authors' Affiliations: 1Division of Hematology, The Comprehensive Can- cer Center, 2Division of Pharmaceutics and 3Medicinal Chemistry, College antagonize microenvironmental stimuli that promote of Pharmacy, 4Center for Biostatistics, 5Department of Chemical and tumor cell survival and can act in a p53-independent Biomolecular Engineering, The Ohio State University, Columbus, Ohio; manner (2, 8). This is beneficial especially to patients who and 6Garden State Cancer Center, Center for Molecular Medicine and Immunology, Morris Plains, New Jersey respond poorly to standard treatment due to p53 chromo- somal abnormalities (1, 9). While corticosteroids are highly Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). active in virtually every type of B-cell malignancy, they have significant side effects, including immunosuppression, fi Y. Mao and G. Trianta llou contributed equally to this work. hyperlipidemia, proximal muscle wasting, and osteoporo- R.J. Lee, J.C. Byrd, and N. Muthusamy are senior authors and contributed sis (10, 11). Developing a strategy to selectively target equally to this work. corticosteroids to B-cell malignancies represents an attrac- Corresponding Authors: Natarajan Muthusamy, The Ohio State Univer- tive treatment approach. sity, 455E, OSUCCC, 410 West 12th Avenue, Columbus, OH 43210. Liposomal delivery can alter drug pharmacokinetics, Phone: 614-292-8135; Fax: 614-292-3312; E-mail: [email protected]; and John C. Byrd, B302 Starling-Loving Hall, which can influence both efficacy and toxicity (12, 13). 320 West 10th Avenue, Columbus, OH 43210. Phone: 614-293-8330; Fax: Examples include clinically approved liposomal daunoru- 614-292-3312; E-mail: [email protected] bicin (Daunoxome; ref. 14) and liposomal doxorubicin doi: 10.1158/1078-0432.CCR-12-2046 (Doxil; ref. 15) that have lower Cmax values and extended Ó2012 American Association for Cancer Research. terminal half-lives as compared with their parental-free www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst December 3, 2012; DOI: 10.1158/1078-0432.CCR-12-2046 Mao et al. cell lines were obtained from the American Type Translational Relevance Culture Collection. Milatuzumab was provided by Immu- Corticosteroids are widely used for the treatment of B- nomedics, Inc. Trastuzumab (Genentech) and goat anti- cell malignancies, including non–Hodgkin lymphoma, human IgG antibody (Fc gamma fragment-specific, anti-Fc, chronic lymphocytic leukemia, and acute lymphoblastic Jackson ImmunoResearch Laboratories) were obtained leukemia; however, this class of drug is associated with commercially. undesirable off target effects. Herein, we developed novel milatuzumab-conjugated liposomes as a targeted Flow cytometry assays dexamethasone carrier for therapeutic delivery in þ Viability was determined by staining with Annexin V- CD74 B-cell neoplasia and explored its effect against FITC (fluorescein isothiocyanate) and propidium iodide the disease. (PI) as described previously (30). Milatuzumab was given at These studies provide preclinical evidence and sup- 5 mg/mL and dexamethasone at 10 mmol/L. For surface port for a potential use of CD74-targeted liposomal staining, CLL cells were washed in PBS and stained with dexamethasone in overcoming dexamethasone-mediat- antibodies to CD19, CD20, CD74 (BD Biosciences) and/or ed adverse effects and as a new therapy for B-cell fluorescence-labeled immunoliposomes. Cells were ana- malignancies. lyzed using a Beckman-Coulter model EPICS XL cytometer (Beckman-Coulter). For internalization studies, 1 Â 106 cells were treated with fluorescently labeled antibodies for 30, 60, and 120 minutes at 37C, washed with glycine acidic drugs and are associated with reduced cardiac toxicity (13). buffer (pH 3) to remove surface-bound antibodies and Liposomal corticosteroids have been evaluated for the processed for flow cytometry as previously described treatment of arthritis and neoplasia in preclinical animal (31). Percent internalization at each time point was models (16–18). Immunoliposomes, which are coated with obtained by the formula: [MFI (exp.) À MFI (0% con- antibodies, can mediate targeted delivery of the payload to trol)]/[MFI (100% control) À MFI (0% control)] Â 100. cells expressing the specific antigen recognized by the anti- MFI is the geometric mean fluorescence intensity; 100% body. Internalizing antibodies have been shown to be control corresponds to CD74 expression on the cell surface superior for therapeutic effects of immunoliposomes of cells treated with PBS alone; and 0% control refers to cells (19–22). There has been limited evaluation of immunoli- incubated with isotype IgG as control at the designated time posomes for delivery of corticosteroids (23, 24), and to points. date, targeted delivery of corticosteroids to B-cell malignan- cies has not been explored. Development of B-cell directed MTS assay immunoliposomes for corticosteroids would require a MTS assay was conducted as previously described (32). B-cell selective target antigen that mediates internalization. Briefly, 1 Â 106 cells were plated in 96-well plates and CD74 has the attributes desired for immunoliposome treated with appropriate drugs for 24 hours. Flavopiridol construction for B-cell–specific targeting of corticosteroids. was used as a positive control. The plates were read 12 hours It is a type II transmembrane protein with increased expres- after addition of MTS solution and at 490 nm, and the sion on the surface of malignant NHL, ALL, and CLL cells absorbance values were normalized to media. and shows robust internalization upon antibody binding (25–27). Milatuzumab, hLL1, is a humanized monoclonal Immunoblot analysis antibody directed against CD74 that internalizes rapidly Immunoblots were conducted as described (30). and is in clinical trials as a potential therapeutic for NHL, Antibodies used included GilZ (Abcam) and glyceralde- ALL, and CLL. We hypothesized that specificity of steroid hyde-3-phosphate dehydrogenase (GAPDH; Santa Cruz treatment could be enhanced using immunoliposomes Biotechnology). coated with milatuzumab. We have shown previously that milatuzumab immunoliposomes (CD74-ILs) potentiate Preparation of immunoliposomes the cytotoxic effect of the antibody, offering advantageous CD74-ILs were prepared as previously described (28). alternative to conventional treatments (28). Using this Briefly, a post-insertion method was used to incorporate vehicle to transport dexamethasone could represent a strat- antibody into preformed liposomes, and CD74-ILs were egy for improving efficacy and reducing systemic toxicity. prepared with antibody-to-lipid ratios of 1:1,000. Methoxy- Herein, we present preclinical
Load more

Recommended publications
  • CD74 Targeted Nanoparticles As Dexamethasone Delivery System for B Lymphoid Malignancies
    CD74 targeted nanoparticles as Dexamethasone Delivery System for B lymphoid malignancies DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Georgia Triantafillou, MPH Integrated Biomedical Sciences Graduate Program The Ohio State University 2011 Dissertation Committee John C. Byrd, MD, advisor Natarajan Muthusamy, PhD co-advisor Robert J.Lee, PhD, co-advisor Mitch A.Phelps, PhD, co-advisor Guido Marcucci, MD committee member Susheela Tridandapani, PhD committee member Copyright page Georgia Triantafillou 2011 ABSTRACT Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia and is not curable with standard therapy. In CLL the B lymphocytes appear morphologically mature but immunologically express less mature B cell makers. Specifically, the CLL B cells co-express surface antigens including CD19, CD20, CD5, CD23. Due to nonspecific delivery of the drugs to malignant as well as normal cells, patients experience numerous side effects. Targeted drug delivery to cancer cells is a desirable goal for all anti cancer strategies. Corticosteroids have been proven to be a beneficial and well established part of CLL treatment. Dexamethasone(DEX) is frequently used in CLL therapies as well as other malignancies and antiinflammatory diseases. However, DEX nonspecifically enters all tissues inducing various toxicities to patients. Therefore, DEX treatment is often discontinued or not administered to certain patients. We aimed to deliver this efficient clinical agent via a targeted delivery vehicle and examine its effect on its target B-CLL cells. The main scope of the work presented is the creation of a sterically stable nanoparticle, an ii immunoliposome (ILP), that has DEX encapsulated in its interior and a monoclonal antibody(Mab) in its exterior targeting CLL B cells expressing the surface antigen that is recognized by the Mab.
    [Show full text]
  • 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]
  • Advances in Anticancer Antibody-Drug Conjugates and Immunotoxins
    Send Orders for Reprints to [email protected] Recent Patents on Anti-Cancer Drug Discovery, 2014, 9, 35-65 35 Advances in Anticancer Antibody-Drug Conjugates and Immunotoxins Franco Dosio1,*, Barbara Stella1, Sofia Cerioni1, Daniela Gastaldi2 and Silvia Arpicco1 1Dipartimento di Scienza e Tecnologia del Farmaco, University of Torino, Torino, I-10125, Italy; 2Dipartimento di Bio- tecnologie Molecolari e Scienze per la Salute, University of Torino, Torino, I-10125, Italy Received: December 13, 2012; Accepted: February 21, 2013; Revised: March 7, 2013 Abstract: Antibody-delivered drugs and toxins are poised to become important classes of cancer therapeutics. These bio- pharmaceuticals have potential in this field, as they can selectively direct highly potent cytotoxic agents to cancer cells that present tumor-associated surface markers, thereby minimizing systemic toxicity. The activity of some conjugates is of particular interest receiving increasing attention, thanks to very promising clinical trial results in hematologic cancers. Over twenty antibody-drug conjugates and eight immunotoxins in clinical trials as well as some recently approved drugs, support the maturity of this approach. This review focuses on recent advances in the development of these two classes of biopharmaceuticals: conventional toxins and anticancer drugs, together with their mechanisms of action. The processes of conjugation and purification, as reported in the literature and in several patents, are discussed and the most relevant results in clinical trials are listed. Innovative technologies and preliminary results on novel drugs and toxins, as reported in the literature and in recently-published patents (up to February 2013) are lastly examined. Keywords: Antibody drug conjugate, anticancer agents, auristatins immunotoxin, calicheamicins, cross-linkers, duocarmycins, maytansinoids.
    [Show full text]
  • Antibody Drug Conjugates in Lymphoma
    Review: Clinical Trial Outcomes Nathwani & Chen Antibody drug conjugates in lymphoma 6 Review: Clinical Trial Outcomes Antibody drug conjugates in lymphoma Clin. Investig. (Lond.) Antibody drug conjugates (ADCs) are comprised of monoclonal antibodies physically Nitya Nathwani1 & Robert linked to cytotoxic molecules. They expressly target cancer cells by delivering cytotoxic Chen*,1 agents to cells displaying specific antigens, and minimize damage to normal tissue. The 1Department of Hematology & Hematopoietic Cell Transplantation, City efficacy and tolerability of these agents are primarily determined by the target antigen, of Hope, Duarte, CA, USA the cytotoxic agent and the linker connecting the cytotoxic agent to the monoclonal *Author for correspondence: antibody. Following advances in technology, clinical trials have demonstrated greater Tel.: +626 256 4673 (ext. 65298) efficacy for ADCs compared with the corresponding naked monoclonal antibodies. Fax: +626 301 8116 This review summarizes the features of current clinically active ADCs in lymphoma and [email protected] emphasizes recent clinical data elucidating the benefit of antibody-directed delivery of cytotoxic agents to tumor cells. Keywords: antibody drug conjugates • lymphoma • monoclonal antibodies Lymphoma is the most common hematologic concentration and poor performance status malignancy, and is subdivided into two main are adverse prognostic factors. SEER (Sur- types: Hodgkin lymphoma (HL) and non- veillance, Epidemiology and End Results) Hodgkin lymphoma (NHL). In the United data from the National Cancer Institute, States, there are an estimated 731,277 people 2013 has revealed a significant improvement 10.4155/CLI.14.73 living with or in remission from lymphoma. in survival rates in this group of diseases in In 2013, there were an estimated 79,030 new the last four decades.
    [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]
  • Daratumumab (Darzalex)
    Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug Clinical Advances in Immunotherapy in Myeloma Webinar 1, June 14, 2017 Monoclonal Antibodies Speakers Moderator: Mary DeRome Multiple Myeloma Research Foundation Norwalk, Connecticut Faculty: Tom Martin, MD University of California, San Francisco San Francisco, California Amy Marsala, MPH, MSN, NP University of California, San Francisco San Francisco, California Gary Rudman, CSP Myeloma Patient Advocate 1 Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug Topics for Discussion • Current and future monoclonal antibodies (what they are, how they work) • Management of side effects in the era of monoclonal antibodies • Patient experience on phase 2 clinical trial of Empliciti (elotuzumab) Tom Martin, MD 2 Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug Current Overall Survival for Newly Diagnosed Myeloma 1.0 89% vs 81% 0.9 Still losing 25% patients in first 3 years 75% vs 62% 0.8 0.7 2007–2011 0.6 0.5 0.4 0.3 Proportion Surviving 2001–2006 0.2 0.1 0.0 012345678910 Years From Diagnosis A good trend but we always need to improve!! Myeloma Treatment: It’s an Art 3 Clinical Advances in Immunotherapy in Myeloma 6/14/17 Webinar 1: Monoclonal Antibodies: A New Type of Myeloma Drug New Agents in Myeloma Therapy Oral Kinase HDAC Immuno- New IMiDs proteasomes inhibitors Novel MOA inhibitors therapies • Lenalidomide
    [Show full text]
  • The Emerging Role of Monoclonal Antibodies in the Treatment of Multiple Myeloma
    Pharmacotherapy 5 The emerging role of monoclonal antibodies in the treatment of multiple myeloma K. Fostier, MD1, R. Schots, MD, PhD1 Monoclonal antibodies have a profound impact on the prognosis and survival of patients with haemato- logical malignancies. In the treatment of multiple myeloma, until recently, results of monoclonal antibodies have been disappointing. The introduction of two novel classes of monoclonal antibodies holds great promise to change this. Daratumumab (and related antibodies) is a monoclonal antibody directed to CD38, an intriguing multifunctional surface protein abundantly expressed on malignant plasma cells and their precursors. Daratumumab displays impressive single agent activity in heavily pretreated multiple myeloma patients and due to its favourable safety profile, this molecule seems to be an excellent accessory companion to known anti-multiple myeloma regimens and also in monotherapy as a maintenance agent. Elotuzumab, to the contrary, is an anti-CS1 monoclonal antibody, which does not show any clinically relevant single agent activity, but when combined with other anti-multiple myeloma drugs appears to greatly enhance their efficacy and can even revert the refractory state to the agents. When these promising results are confirmed in phase III trials, immunotherapy can finally be incorporated in the treatment schedule of newly diagnosed and relapsed/refractory multiple myeloma patients. (Belg J Hematol 2015;6(5):209-15) Introduction enter the clinical field. Rituximab (an anti-CD20 mAb) has significantly im- The new anti-CD38 and anti-CS1 mAbs show great proved survival in several B-cell malignancies including promise in the treatment of MM. This review briefly non-Hodgkin’s lymphoma, chronic lymphocytic leu- summarises the physiological role of these two surface kaemia and Waldenström’s macroglobulinemia.
    [Show full text]
  • Hematology Drugs in the Pipeline
    102 HemOnc today | NOVEMBER 25, 2015 | Healio.com/HemOnc Hematology Drugs in the Pipeline HEMONC TODAY presents the most recent information about hematology drugs in the pipeline. Drugs listed here are in phase 2 or phase 3 development for a variety of indications. Clinicians can use this chart as a quick reference to learn about the status of those drugs that may be clinically significant to their practice. To view the entire chart online, go to www.Healio.com/HematologyPipeline. Generic name (Brand name, Manufacturer) Indication(s) Development status A6 peptide (Angstrom Pharmaceuticals) chronic lymphocytic leukemia, small lymphocytic lymphoma phase 2 AAV5-hFIX (UniQure Biopharma) hemophilia phase 2 ABC294640 (RedHill Biopharma) diffuse large B-cell lymphoma phase 2 abemaciclib (Eli Lilly) mantle cell lymphoma phase 2 abexinostat (Pharmacyclics) follicular lymphoma, mantle cell lymphoma phase 2 ABP 798 (Allergan/Amgen) non-Hodgkin’s lymphoma phase 3 ACP-196 (Acerta Pharma) B-cell malignancies (combination therapy), mantle cell lymphoma phase 2 READ PERSPECTIVE on this drug from Richard R. chronic lymphocytic leukemia phase 3 Furman, MD, on page 108. ACP-319 (Acerta Pharma) B-cell lymphoma (combination therapy), chronic lymphocytic leukemia phase 2 (combination therapy) adeno-associated virus serotype 8 Factor IX gene therapy hemophilia B phase 2 (AskBio009, Baxalta) AEB071 (Novartis) diffuse large B-cell lymphoma (combination therapy for CD79-mutant or phase 2 ABC-subtype disease) AFM 13 (Affimed Therapeutics) Hodgkin’s lymphoma phase
    [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]
  • Antibody-Drug Conjugates: a Comprehensive Review
    Author Manuscript Published OnlineFirst on October 28, 2019; DOI: 10.1158/1541-7786.MCR-19-0582 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Antibody-Drug Conjugates: A Comprehensive Review Puregmaa Khongorzul1, Cai Jia Ling1, Farhan Ullah Khan2, Awais Ullah Ihsan3, Juan Zhang1* 1. Antibody Engineering Laboratory, School of Life Science & Technology, China Pharmaceutical University, Nanjing, China 2. Shanghai Jiao Tong University, School of Pharmacy, 800 Dongchuan Road, Shanghai, 200240, China 3. Immunology Division, Faculty of Medicine and Health Sciences, Department of Pediatrics, Université de Sherbrooke, 3001 North 12th avenue, Sherbrooke, QC, J1H 5N4, Canada *Correspondence to: Juan Zhang Professor at the School of Life Science & Technology China Pharmaceutical University, Nanjing, China Phone: +862583271483 Email: [email protected] ORCID (Juan Zhang):0000-0003-1067-7878 Running title: Antibody-Drug Conjugates in Cancer Immunotherapy. Keywords: Cancer; antibody-drug conjugates; antibody; linker; payload; treatment Declaration of interests All authors declare no competing interests. 1 Downloaded from mcr.aacrjournals.org on September 24, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 28, 2019; DOI: 10.1158/1541-7786.MCR-19-0582 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Antibody-drug conjugates (ADCs) are one of the fastest-growing anti-cancer drugs. This approach comprises a monoclonal antibody conjugated to the cytotoxic payload via a chemical linker that directed towards a target antigen expressed on the cancer cell surface, reducing systemic exposure and therefore toxicity. ADCs are complex molecules that require careful attention to various components.
    [Show full text]
  • Monoclonal Antibodies for the Treatment of Multiple Myeloma: an Update
    International Journal of Molecular Sciences Review Monoclonal Antibodies for the Treatment of Multiple Myeloma: An Update Hanley N. Abramson Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202, USA; [email protected] Received: 24 October 2018; Accepted: 5 December 2018; Published: 7 December 2018 Abstract: The past two decades have seen a revolution in multiple myeloma (MM) therapy with the introduction of several small molecules, mostly orally effective, whose mechanisms are based on proteasome inhibition, histone deacetylase (HDAC) blockade, and immunomodulation. Immunotherapeutic approaches to MM treatment using monoclonal antibodies (mAbs), while long in development, began to reap success with the identification of CD38 and SLAMF7 as suitable targets for development, culminating in the 2015 Food and Drug Administration (FDA) approval of daratumumab and elotuzumab, respectively. This review highlights additional mAbs now in the developmental pipeline. Isatuximab, another anti-CD38 mAb, currently is under study in four phase III trials and may offer certain advantages over daratumumab. Several antibody-drug conjugates (ADCs) in the early stages of development are described, including JNJ-63723283, which has attained FDA breakthrough status for MM. Other mAbs described in this review include denosumab, recently approved for myeloma-associated bone loss, and checkpoint inhibitors, although the future status of the latter combined with immunomodulators has been clouded by unacceptably high death rates that caused the FDA to issue clinical holds on several of these trials. Also highlighted are the therapies based on the B Cell Maturation Antigen (BCMA), another very promising target for anti-myeloma development. Keywords: myeloma; daratumumab; elotuzumab; isatuximab; CD38; JNJ-63723283; denosumab; checkpoint inhibitors; BCMA; bispecific T-cell engager; antibody-drug conjugates 1.
    [Show full text]