• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
A. Stathis - Lymphomas - New drugs in the treatment of lymphomas
 

A. Stathis - Lymphomas - New drugs in the treatment of lymphomas

on

  • 2,080 views

 

Statistics

Views

Total Views
2,080
Views on SlideShare
2,079
Embed Views
1

Actions

Likes
0
Downloads
0
Comments
0

1 Embed 1

http://www.easoncology.net 1

Accessibility

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • ARZ1009/025/1 Ocrelizumab (Humanized version of murine 2H7 Ab) Potent inducer of antibody-dependent cellular cytotoxicity (ADCC) Low immunogenicity Ofatumumab Uniquely binds to the small and large loops of CD20, enabling binding closer to the cell membrane 3 Is a potent and effective activator of CDC and ADCC in CD20+ B cells 3,4 TRU-015 - Small modular immunopharmaceutical drug composed of human IgG1 Fc and hinge regions (hinge, CH2, and CH3) linked directly to an anti-CD20 scFv Veltuzumab (based on the IgG construct used in epratuzumab) Fewer infusion-related adverse events compared to rituximab Encouraging overall response rates (ORRs)/complete response rates in Phase III clinical trial AME-133v Increased binding affinity to Fc δ R IIIa (CD16) compared with rituximab 10-fold increase cytotoxicity compared with rituximab PRO131921(version 114) – engineered, humanized 2H7 Evaluated in autoimmune diseases and relapsed/refractory follicular lymphoma Greater binding affinity to Fc δ R IIIa compared with rituximab Augmented ADCC compared with rituximab GA101– glycol-engineered Fc portion + modified elbow hinge 10–100-fold increase in ADCC compared to rituximab Induces apoptosis Greater direct growth arrest compared with rituximab reduced CDC References 1. Beers SA, et al. Type II (tositumomab) anti-CD20 monoclonal antibody out performs type I (rituximab-like) reagents in B-cell depletion regardless of complement activation. Blood 2008; 112( 10): 4170–4177 2. Bello C, Sotomayor EM. Monoclonal antibodies for B-cell lymphomas: rituximab and beyond. Hematology Am Soc Hematol Educ Program ; 2007 : 233–242 3. Teeling JL, et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol 2006; 177 (1): 362–371 4 . Teeling JL, et al. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood 2004; 104 (6): 1793–1800 5. G.A. Salles G.A et al. A phase I/II study of RO5072759 (GA101) in patients with relapsed/refractory CD20+ malignant disease, Blood 2008, 112 (11) [Abstract 234].
  • ARZ1009/025/1 Key point: Antibody technology has moved forward since the introduction of rituximab Chimeric mAbs have variable regions derived from murine sequences whereas the constant region is human Rituximab (Mabthera ® [Roche, Europe]/Rituxan ® [Genentech/ Biogen Idec, United States]) – type I mAb In contrast, humanized mAbs are constructed with only the antigen-binding regions derived from murine sequences Veltuzumab (IMMU-106 [Immunomedics]) – type I mAb Ocrelizumab ( PRO70769 [Genentech]) – type I mAb Completely human mAbs can be generated by transgenic mice genetically engineered to recapitulate the human antibody response by introducing the human immunoglobulin loci into the mouse germ line Ofatumumab (ARZERRA [GSK]) – type I mAb Humanized engineered mAbs AME-133v (Eli Lilly & Co) – type I mAb PRO-131921 (Genentech) – type I mAb GA-101 (Roche) – type II mAb References Press O, et al. Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B cell lymphomas. Blood 1987; 69 : 584–591 Bello C, Sotomayor EM. Monoclonal antibodies for B-cell lymphomas: rituximab and beyond. Hematology Am Soc Hematol Educ Program; 2007 : 233–242
  • ARZ1009/025/1 The B-cell-specific, cell surface antigen CD20 is an excellent target for therapeutic mAbs For any therapeutic antibody to be effective, its specific target must be stably expressed, enabling sustained binding: Expression of CD20 in B cells has been shown to be highly stable CD20 is expressed at most stages of B-cell development and is highly expressed on the cell surface of at least 95% of malignant B cells CD20 is not expressed at the earliest stages of B-cell lineage commitment or in terminally differentiated plasma cells, which produce antibodies to a variety of pathogens 1-3 To effectively kill B cells, mAbs must bind epitopes in close proximity to the plasma membrane Facilitates the recruitment of cytotoxic effectors (both cells and proteins) to the B-cell surface 1,3 CD20 spans the cellular membrane four times 1,3 The large extracellular loop is located between the third and fourth transmembrane region The small extracellular loop is located between the first and second transmembrane regions and is in very close proximity to the cellular membrane Both the C terminal and N terminal ends of the molecule are intracellular CD20 is unlikely to exist in the plasma membrane in a monomeric form and is proposed to form tetramers 1,4 Studies have demonstrated that that CD20 is not usually internalized or shed 2,3 The CD20 antigen has no known ligand and its function is not completely understood Studies suggest that it may act as an ion channel regulating calcium flux CD20 may also be involved in B-cell receptor activation and signalling Studies have demonstrated that CD20-deficient mice are perfectly viable and demonstrate a normal phenotype, suggesting that there may be redundancy in its functions 1-3 References 1. Cragg MS, et al. The biology of CD20 and its potential as a target for mAb therapy. Curr Dir Autoimmun 2005; 8 : 140–174 Hotta T. Anti-CD20 monoclonal antibody as a new treatment modality for B-cell lymphoma. Acta Histochem Cytochem 2002; 35 (4): 275–279 Teeling JL, et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol 2006; 177 (1): 362–371 Glennie MJ, et al. Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol 2007; 44 (16): 3823 – 3837
  • ARZ1009/025/1 CD20 antigen is first expressed during early pre-B-cell development and ceases expression during terminal plasma cell differentiation 1-3 As CD20 is not expressed in haematopoietic stem cells, mAbs binding this target are unlikely to inhibit the development of non-B-cell haematopoietic lineages, such as erythrocytes (red blood cells), granulocytes( basophills, eosinophils and neutrophils) and platelets 1-3 In addition, after mAb therapy, there may be B-cell recovery from spared pro-B cells and stem cells 1-3 Studies have demonstrated that CD20 is not expressed on plasma cells, which produce antibodies that are crucial for defence against pathogens; therefore, therapeutic mAbs recognizing this target should not significantly inhibit the ability of plasma cells to produce antibodies to a wide variety of pathogens 1-3 CD20 is highly expressed in developing B cells that give rise to NHL and CLL, making it an excellent mAb target for the treatment of these diseases 1-3 References Cragg MS, et al. The biology of CD20 and its potential as a target for mAb therapy. Curr Dir Autoimmun 2005; 8 : 140–174 Hotta T. Anti-CD20 monoclonal antibody as a new treatment modality for B-cell lymphoma. Acta Histochem Cytochem 2002; 35 (4): 275–279 O'Connor OA. Emerging role of next generation anti-CD20 monoclonal antibodies in B-cell lymphomas. Presented at: Optimizing Strategies for Targeting CD20 in B-cell Lymphoproliferative Disorders Satellite Symposium; June 7, 2007; held in conjunction with the 12th Annual Congress of the European Hematology Association; June 7–10 2007; Vienna, Austria
  • ARZ1009/025/1 Studies have demonstrated that anti-CD20 mAbs can destroy CD20+ cells by three distinct mechanisms: CDC, ADCC and apoptosis 1,2 In CDC, mAb binding to its specific target results in the recruitment of complement; ultimately, this results in the generation of the membrane attack complex (MAC), which punches holes in the B-cell plasma membrane, causing osmotic lysis of the cell 1-3 ADCC is a cell-mediated process by which effector cells such as neutrophils, natural killer cells and macrophages bind to the mAbs via their Fc receptors and release cytotoxic agents that destroy the cell 1-3 The binding of a mAb to its target cell results in the activation of specific intracellular signalling pathways that trigger apoptosis of the cell 1-3 In addition to the above-mentioned mechanisms, it has been postulated that rituximab-induced killing of malignant B cells might result in priming of lymphoma antigen - specific T-cell responses, or a vaccinal effect, which may be responsible for a sustained anti-lymphoma immunity 1 It is also possible that mAbs may induce cell death by altering the physiological function of CD20 in B cells 3 References 1.Bello C, Sotomayor EM. Monoclonal antibodies for B-cell lymphomas: rituximab and beyond. Hematology Am Soc Hematol Educ Program ; 2007 : 233–242 2.Glennie MJ, et al. Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol 2007; 44 (16): 3823–3837 3.Jazirehi AR and Bonavida B. Cellular and molecular signal transduction pathways modulated by rituximab (rituxan, anti-CD20 mAb) in non-Hodgkin's lymphoma: implications in chemosensitization and therapeutic intervention. Oncogene 2005; 24 (13): 2121–2143
  • ARZ1009/025/1 Two distinct types of CD20 mAb have been identified: 1-3 Type I CD20 mAbs, which are rituximab-like 1-3 Induce clustering of CD20 molecules into detergent-insoluble microdomains known as lipid rafts Clustering enhances the recruitment of C1q and CDC Are relatively poor at inducing apoptosis Are efficient at ADCC Ofatumumab is a type I anti-CD20 mAb 2 Type II CD20 mAb 1-3 Are incapable of inducing CD20 clustering Are inefficient at recruiting C1q and do not induce CDC Can induce ADCC Type II mAbs can induce B-cell apoptosis by triggering death signals that activate apoptosis Studies have demonstrated that at saturation, the number of type I mAbs bound to each B cell is twice that of type II mAbs 2 Type II anti CD20 mAbs include: Radiolabelled anti-CD20 mAbs, such as: Ibritumomab (Zevalin ® ) – FDA approved 2002 4 Tositumomab – FDA approved 2003 4 GA101, a humanized anti-CD20 mAb with high affinity for FcR γ III, which results in enhanced ADCC and strong caspase-independent apoptosis activity upon CD20 binding 5 – investigational drug References 1. Cragg MS, et al. The biology of CD20 and its potential as a target for mAb therapy. Curr Dir Autoimmun 2005; 8 : 140–174 2. Glennie MJ, et al. Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol 2007; 44 (16): 3823–3837 3. Teeling JL, et al. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood 2004; 104 (6): 1793–1800 4. Du, J et al. Structure of the Fab fragment of therapeutic antibody ofatumumab provides insights into the recognition mechanism with CD20. Mol Immunol 2009; 46 (11-12): 2419–2423 5. Quintás-Cardama A and O ’ Brien S. Targeted therapy for chronic lymphocytic leukemia. Targ Oncol 2009; 4 : 11–21
  • ARZ1009/025/1 A variety of mechanisms inducing rituximab resistance has now been identified Studies demonstrate that rituximab ’ s cell-killing efficacy is positively correlated with CD20 density on the B-cell plasma membrane 1-3 Low CD20 density on CLL cells may explain why rituximab has limited efficacy in the treatment of CLL 1-3 B cells express a variety of cell surface proteins CD55 and CD59 are B-cell surface proteins with complement inhibitory function Overexpression of these molecules can result in significantly reduced complement-mediated cell killing by rituximab 4,5 Polymorphisms in the gene for the FcR found on effector cells may significantly alter FcR structure/function, reducing or eliminating its ability to bind rituximab ’ s Fc region, which results in reduced CDC activity 6 The use of high-dose rituximab treatment for B-cell malignancies may lead to exhaustion of cell killing effector cells, resulting in reduced ADCC-mediated B-cell killing Exhausted effector cells may induce the removal (shaving) of CD20 molecules on the B-cell plasma membrane, further reducing rituximab ’ s cell killing capability 7,8 The use of rituximab may lead to down-regulation of pro-apoptotic proteins, which may result in resistance to co-administered chemotherapy 9 References 1. van Meerten T, et al. Complement-induced cell death by rituximab depends on CD20 expression level and acts complementary to antibody-dependent cellular cytotoxicity. Clin Cancer Res 2006; 12 (13): 4027–4035 2. Golay J, et al. CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59. Blood 2001; 98 (12): 3383–3389 3. Czuczman MS, et al. Acquirement of rituximab resistance in lymphoma cell lines is associated with both a global CD20 gene and protein down-regulation regulated at the pretranscrpitional and posttranscriptional level. Clin Cancer Res 2008; 14 (5): 1561–1570 4. Cillessen SAGM, et al. Chemotherapy-refractory diffuse large B-cell lymphomas (DLBCL) are effectively killed by ofatumumab-induced complement-mediated cytoxicity. Poster presented at: 49 th Annual Meeting and Exposition of the American Society of Hematology; December 8–10, 2007; Atlanta, GA. [Abstract 2346]. Blood 2007; 110 (11) 5. Golay J, et al. Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood 2000; 95 (12): 3900–3908 6. Friedberg JW. Unique toxicities and resistance mechanisms associated with monoclonal antibody therapy. Hematology Am Soc Hematol Educ Program 2005: 329–334 7. Beum PV, et al. The shaving reaction: rituximab/CD20 complexes are removed from mantle cell lymphoma and chronic lymphocytic leukemia cells by THP-1 monocytes. J Immunol 2006; 176 (4): 2600–2609 8. Williams ME, et al. Thrice-weekly low-dose rituximab decreases CD20 loss via shaving and promotes enhanced targeting in chronic lymphocytic leukemia. J Immunol 2006; 177 (10): 7435–7443 9. Olejniczak SH, et al. Acquired resistance to rituximab is associated with chemotherapy resistance resulting from decreased Bax and Bak expression. Clin Cancer Res 2008; 14 (5): 1550–1560
  • ARZ1009/025/1 Key point: Ofatumumab binding to a unique CD20 epitope is reportedly linked to more efficient complement activation Ofatumumab binding to the small extracellular loop appears linked to efficient C1q capture and more potent CDC in vitro : Compared with rituximab-binding to the large loop, interaction with the small loop positions ofatumumab closer to the membrane. The close proximity of the Fc regions to the target membrane may enhance complement activation due to the short half-life of active complement enzymes 1 Alternatively, binding to the small loop could promote more efficient translocation into lipid rafts, which is associated with binding and activation of C1q 2 The clinical significance of binding to the small loop epitope is unknown, but currently under investigation in clinical trials The antigen-combining site of the Fab fragment of ofatumumab is composed of a large deep pocket, composed of six complementarity determining region loops 3 This pocket has a hydrophobic periphery and positively charged bottom 3 Structural analysis and comparison with other antibodies suggest that: 3 The hydrophobic periphery may interact with the epitope on CD20 that is enriched with hydrophobic residues and is very close to the cell membrane The positively charged bottom may interact with Glu150 of CD20, the only negatively charged residue within this epitope Closer binding to the B-cell membrane enables ofatumumab clustering and leads to rapid engagement and activation of the complement system, 4 inducing more rapid and powerful CDC compared with rituximab in vitro 5 References Teeling JL, et al. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood 2004; 104 (6): 1793–1800 Cragg MS, et al. Complement-mediated lysis by anti-CD20 mAb correlates with segregation into lipid rafts. Blood 2003; 101 : 1045 –52 Du, J et al. Structure of the Fab fragment of therapeutic antibody ofatumumab provides insights into the recognition mechanism with CD20. Mol Immunol 2009; 46 (11-12):2419–2423 Beum PV, et al. Complement activation on B lymphocytes opsonized with rituximab or ofatumumab produces substantial changes in membrane structure preceding cell lysis. J Immunol 2008; 181 : 822–832 Pawluczkowycz A, et al. Binding of submaximal C1q promotes complement-dependent cytotoxicity (CDC) of B cells opsonized with anti-CD20 mAbs ofatumumab (OFA) or rituximab (RTX): considerably higher levels of CDC are induced by OFA than by RTX. J Immunol 2009; 183 : 749–758
  • ARZ1009/026/1 Key point: Data from the phase I/II study of single-agent ofatumumab in relapsed/refractory CLL demonstrates the feasibility of CD20-targeted therapy in B cell malignancies An objective response rate of 50% was achieved in patients from cohort C who received the 2000 mg dose Median progression-free survival was 15 weeks The maximum tolerated dose for ofatumumab was not reached More than 50% of relapsed or refractory CLL patients treated with ofatumumab experienced a reduction in lymphadenopathy, and most patients had a reduction in circulating CLL cells 56% of adverse events (AEs) related to the first infusion of ofatumumab Infusion-related AEs reduced in number and intensity at each subsequent infusion The 2000 mg dose of ofatumumab was selected as the going forward dose based on the results of this Phase I/II study in pretreated CLL patients, the majority of whom had Rai stage I/II disease: Patients were treated with four doses of ofatumumab at three different dosages (500, 1000 and 2000 mg) All response that had a duration greater than 2 months were achieved with the 2000 mg dose 13/27 patients in the 2000 mg group had responses for a median duration of 15 weeks No dose related safety issues at 2000mg to prevent further development at this dosage in CLL Reference Coiffier B, et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a Phase 1-2 study. Blood 2008; 111 (3): 1094–1110.
  • ARZ1009/026/1 Key point: Data from the phase I/II study of single-agent ofatumumab in relapsed/refractory CLL demonstrates the feasibility of CD20-targeted therapy in B cell malignancies An objective response rate of 50% was achieved in patients from cohort C who received the 2000 mg dose Median progression-free survival was 15 weeks The maximum tolerated dose for ofatumumab was not reached More than 50% of relapsed or refractory CLL patients treated with ofatumumab experienced a reduction in lymphadenopathy, and most patients had a reduction in circulating CLL cells 56% of adverse events (AEs) related to the first infusion of ofatumumab Infusion-related AEs reduced in number and intensity at each subsequent infusion The 2000 mg dose of ofatumumab was selected as the going forward dose based on the results of this Phase I/II study in pretreated CLL patients, the majority of whom had Rai stage I/II disease: Patients were treated with four doses of ofatumumab at three different dosages (500, 1000 and 2000 mg) All response that had a duration greater than 2 months were achieved with the 2000 mg dose 13/27 patients in the 2000 mg group had responses for a median duration of 15 weeks No dose related safety issues at 2000mg to prevent further development at this dosage in CLL Reference Coiffier B, et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a Phase 1-2 study. Blood 2008; 111 (3): 1094–1110.
  • ARZ1009/026/1 Key point: Data from the phase I/II study of single-agent ofatumumab in relapsed/refractory CLL demonstrates the feasibility of CD20-targeted therapy in B cell malignancies An objective response rate of 50% was achieved in patients from cohort C who received the 2000 mg dose Median progression-free survival was 15 weeks The maximum tolerated dose for ofatumumab was not reached More than 50% of relapsed or refractory CLL patients treated with ofatumumab experienced a reduction in lymphadenopathy, and most patients had a reduction in circulating CLL cells 56% of adverse events (AEs) related to the first infusion of ofatumumab Infusion-related AEs reduced in number and intensity at each subsequent infusion The 2000 mg dose of ofatumumab was selected as the going forward dose based on the results of this Phase I/II study in pretreated CLL patients, the majority of whom had Rai stage I/II disease: Patients were treated with four doses of ofatumumab at three different dosages (500, 1000 and 2000 mg) All response that had a duration greater than 2 months were achieved with the 2000 mg dose 13/27 patients in the 2000 mg group had responses for a median duration of 15 weeks No dose related safety issues at 2000mg to prevent further development at this dosage in CLL Reference Coiffier B, et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a Phase 1-2 study. Blood 2008; 111 (3): 1094–1110.
  • Lenalidomide has a dual mechanism of action. It reduces multiple myeloma tumors through both tumoricidal and immunomodulatory activities Tumoricidal activities include induction of cell growth arrest and apoptosis Dexamethasone added to lenalidomide results in synergistic activation of TSG and caspases Immunomodulatory activities include enhancement of activation of T cells, NK cells, and NKT cells, reduction of T reg numbers, and induction of anti-tumor immune responses. Additionally, lenalidomide reverses immunosuppression through its activities on T and NK cells, as well as by directly reducing the numbers of MM cells. References . Hideshima, T et al. Blood. 2000;96:2943-2950 . Verhelle D et al. Cancer Res 2007;67(2):746–55. Schafer PH et al. XII International Myeloma Workshop. 2009. abstract #B444 . Mitsiades, N. et al. Blood . 2002;99:4525-4530. Schafer PH et al. JPET 2003; 305:1222–1232. Haslett PA et al. J Infect Dis. 2003 Mar 15;187(6):946-55 Davies FE, et al. Blood. 2001;98:210-216. Chang DH, et al. Blood . 2006;108:618-621. Noonan KA, et al. ASH Annual Meeting Abstracts . 2008;Abstract 2772. Ramsay AG et al. J Clin Invest. 2008;118(7):2427-37. Tai YT et al. Cancer Res. 2005;65(24):11712-20. Wu L et al. Clin Cancer Res. 2008;14(14):4650-7.

A. Stathis - Lymphomas - New drugs in the treatment of lymphomas A. Stathis - Lymphomas - New drugs in the treatment of lymphomas Presentation Transcript

  • New drugs for the treatment of lymphomas Anastasios Stathis, MD New Drugs Program and Lymphoma Unit (IOSI) Oncology Institute of Southern Switzerland 3 RD EASO Masterclass in Clinical Oncology Amman,27-29 Oct 2011
  • Introduction
    • In 2010 around 75.000 people were diagnosed with NHL in Europe
    • For the most common subtypes the addition of rituximab to chemotherapy has significantly improved outcomes
    • However death rates are significant ( 31000 in 2010 in Europe)
    • New drugs are needed
  • Drug development for lymphomas
    • Slow process with only few drugs approved
    • No new drugs approved for HL over the last 30 years
    • High attrition rate in the development of anticancer agents
    • Only a minimal proportion of approval applications in onco-hematology have resulted in approved drugs for lymphomas
  • Outline
    • Monoclonal antibodies
    • Small molecules
    • Future directions
  • Monoclonal antibodies
    • B-cell lineage antigens
    • Other antigens (CD30,CD40,CD80)
    • CD19, CD22, CD37
    • CD20
    • Free MoAb (CDC, ADCC, Apoptosis)
    • Conjugated to chemo (cytotoxic)
    Target Mechanism of action
  • IgG 1 =immunoglobulin G 1 ; CDC=complement-dependent cytotoxicity; iNHL=indolent non-Hodgkin's lymphoma; ADCC=antibody-dependent cellular cytotoxicity; SMIP=small modular immunopharmaceutical drug; RA=rheumatoid arthritis; ITP=idiopathic thrombocytopenic purpura; mAb=monoclonal antibody Old target, new drugs: CD20-MoAbs Phase III for CLL, phase II for iNHL, DLBCL Human (Ig transgenic mice) IgG 1 with high CDC I Ofatumumab   Antibody Antibody Type Format Stage of development RO 045-2294 I Subcutaneous Rituximab Phase III, iNHL Ocrelizumab (PRO-70769) I Humanized IgG 1 (2H7) with increased binding to Fc γ RIIIa and decreased CDC Phase III trials for NHL and autoimmune conditions Veltuzumab (Ah20) I Humanized (similar binding and activity to rituximab) Phase I/II in iNHL and ITP (including subcutaneous route) AME-133v I Humanized IgG 1 selected for increased binding to CD20 and FcRIIIa, leading to augmented ADCC Phase I/II in relapsed NHL PRO-131921 (version 114) I Humanized IgG 1 version of LyB-1 with elbow mutations and modified Fc glycosylation giving augmented ADCC and apoptosis Phase I/II in CLL and NHL GA-101 II Humanized, glyco-engineered, type II mAb: increased ADCC and apoptosis but reduced CDC killing Phase III DLBCL, iNHL
  • New generation of anti-CD20 mAbs Veltuzumab Ocrelizumab Ofatumumab AME-133v GA-101 PRO-31921 Murine Chimeric Humanized Fully human Engineered 1987 1994 1997 2006 2009 1f5 “ serotherapy ” in 4 pts with refractory B-cell carcinoma CD2B: phase I study in pts with recurrent B-cell lymphoma Rituximab: FDA approval for relapsed or refractory, low grade, CD20+, B-cell NHL Rituximab: approved for first-line use in B-cell lymphomas Ofatumumab : approved in US for CLL refractory to fludarabine and alemtuzumab Rituximab: approved in Europe for untreated and relapse/refractory CLL mAb=monoclonal antibody; pts=patients; FDA=Food and Drug Administration (US); NHL=non-Hodgkin ’ s lymphoma
    • Expressed:
      • Exclusively on B cells
      • On most B cells in periphery
      • On most malignant B cells
    • Stable on B-cell surface, allowing sustained mAb binding
      • Some reports indicate that it is infrequently internalized or shed
    • Function not well understood but believed to contribute to B-cell growth, proliferation, differentiation and activation
      • No known ligand
      • May form a membrane ion channel and play a role in calcium flux
      • Involved in B-cell receptor activation and signalling
    CD20: attractive target for the treatment of B-cell malignancies B cell CD20 Large loop Small loop B-cell membrane
  • Haematopoietic stem cell Bone Marrow Blood, Lymph CML Precursor B-cell acute leukaemias Myeloma Lymphoid stem cell Pro- B cell Pre-B cell Immature B cell Mature B cell Activated B cell Memory B cell Plasma cell CD20+
    • CD20 expression begins at early pre-B cell stage, is largely lost during plasma cell differentiation 1-2
      • Present on stages that give rise to CLL and B-cell lymphomas
      • Not present on essential cells, including haematopoietic stem cells and antibody-producing plasma cells
    B-cell lymphomas CLL 1 Cragg MS, et al. Curr Dir Autoimmun 2005; 8 : 140–174; 2 O'Connor OA. Presented at: Optimizing Strategies for Targeting CD20 in B-cell Lymphoproliferative Disorders Satellite Symposium; June 7, 2007; held in conjunction with the 12th Annual Congress of the European Hematology Association; June 7–10 2007; Vienna, Austria CML=chronic myeloid leukaemia; CLL=chronic lymphocytic leukaemia CD20: expressed at key stages of B-cell development
    • CDC 1-3
    • ADCC 1-3
    • Apoptosis 1-3
    Anti-CD20 mAbs mechanism of action 1 Bello C, Sotomayor EM. Hematology Am Soc Hematol Educ Program ; 2007 : 233–242; 2 Glennie MJ, et al. Mol Immunol 2007; 44 (16): 3823–3837; 3 Jazirehi AR, Bonavida B. Oncogene 2005; 24 (13): 2121–2143 ADCC=antibody-dependent cellular cytotoxicity; CDC=complement-dependent cytotoxicity; MAC=membrane attack complex C1q mAb CD20 B cell MAC Macrophage
  • 1 Cragg MS, et al. Curr Dir Autoimmun 2005; 8 : 140–174; 2 Glennie MJ, et al. Mol Immunol 2007; 44 (16): 3823–3837; 3 Teeling JL, et al. Blood 2004; 104 (6): 1793–1800 Differences between type I and type II anti-CD20 mAbs 1-3 – = no activity; + = some activity; ++ = significant activity Type I Type II mAb=monoclonal antibody; CDC=complement-dependent cytotoxicity; ADCC=antibody-dependent cellular cytotoxicity Anti-CD20 mAbs: two types Type I Type II CD20 clustering in B-cell membrane ++ - Induction of CDC ++ + Induction of ADCC ++ ++ Induction of apoptosis + ++
    • Low CD20 density
      • Rituximab requires high CD20 density for CDC
      • Limited efficacy in CLL may be due to relatively low CD20 density
    • Complement inhibition 3,4
      • B-cell overexpression of complement inhibitory proteins, for example CD55 and CD59, may reduce rituximab-mediated CDC
    Potential mechanisms for rituximab limitations Lower rituximab-induced CDC correlates with lower CD20 density 1 *Antibodies bound per cell = number of CD20 molecules per cell 100 80 60 40 20 0 0 1.0x10 5 2.0x10 5 3.0x10 5 4.0x10 5 5.0x10 5 6.0x10 5 7.0x10 5 8.0x10 5 CLL Lymphoma % CDC CD20-ABC*
  • Ofatumumab
    • A novel, human monoclonal antibody developed for the treatment of refractory CLL
    • Targets both the small and large loop epitopes on CD20
    • Exhibits enhanced binding to, and slow dissociation from, CD20 in vitro
    • Enables CD20-mediated cell lysis in vitro in cells with low CD20 expression or in rituximab-resistant cells
  • Ofatumumab targets a unique CD20 epitope on the small extracellular loop Schematic diagram of the structure of CD20 Ofatumumab binding site Rituximab binding site Large loop Small loop B-cell membrane
  • Ofatumumab in CLL
    • Well tolerated in patients with CLL in doses up to 2000 mg (MTD not reached)
    • Infusion-related AEs:
      • 56% of AEs reported on the day of infusion
      • reduced at each subsequent infusion
    • 2000 mg selected as RP2D as all response with a duration >2 months were achieved with this dose
    • Considerable single-agent activity in the treatment of refractory CLL patients:
      • ORR: 50% , PFS: 15 weeks
  • Ofatumumab-further clinical development
    • Is it better than Rituximab?
    • In P2T of relapsed FL, 42% RR (not different from R)
    • Ongoing phase II and III studies in iNHL and DLBCL
  • GA -101
    • Humanized glyco-engineered MoAb
    • High affinity binding to CD20
    • Type II binding to the epitope: low complement-dependent cytotoxicity
    • Increased antibody-dependent cellular toxicity (ADCC) and direct cell-death induction (compared to rituximab)
    • Greater efficacy than Rituximab in carriers of the Fc  RIIIa low affinity receptor polymorphism
  • Salles, ASH 2010 # 2868 (Poster) GA-101 in Heavily Pre-treated R/R iNHLs
    • RR: 17% (LD)
    • RR: 55% (HD)
    n=40, median 4 prior lines, 60% refractory to Rituximab, 25% post auto SCT LD Cohort 400, n=18 & HD Cohort 1600/800, n=22
    • n=40, 3 previous lines, 63% refractory to Rituximab
    • LD Cohort 400, n=21  DLBCL 10, MCL 11
    • HD Cohort 1600/800, n=19  DLBCL 15, MCL 4
    Cartron, ASH 2010 # 2878 (Poster) GA-101 in Heavily Pre-treated R/R DLBCL and MCL ORR for LD ORR for HD CR All cases 24% 32% DLBCL 30% 27% 0/24 MCL 18% 50% 2/15 Median PFS 78 days 83 days
  • Salles, ASH 2010 # 2868 (Poster) GA-101 in Heavily Pre-treated R/R iNHLs
    • RR: 17% (LD)
    • RR: 55% (HD)
  • GA101-current clinical development
    • Is it better than Rituximab?
    • Ongoing 1st line study with chemo (Benda or CHOP) in FL
    • New phase III trial in DLBCL, 1st line
      • G-CHOP vs R-CHOP
  • Subcutaneous rituximab
    • To simplify treatment, especially for maintenance therapy
    • Drug together with hyaluronidase
    • Rash, erythema, mild discomfort, no general reactions
  • Subcutaneous rituximab
    • Results of phase Ib study in iNHL showed comparable concentrations at C trough for SC 625-800mg/sm and IV 375mg/sm
    • Dose for further studies: flat dose 1400mg SC
    • Phase III induction + long term maintenance study in iNHL that have relapsed after R-chemo
  • Monoclonal antibodies against other B-cell lineage antigens 19, 3 19 22 22 CD I/II FL, MCL , ALL bispecific T cell engager Blinatumomab (MT103) Aggressive, Indolent Aggressive, Indolent Indolent, DLBCL Population I/II conjugated to a tubulin inhibitor SAR3419 III humanized, conjugated to calicheamicin Inotuzumab Ozogamicin III IgG1 humanized Epratuzumab Phase Specificity Agent
  • Inotuzumab Ozogamicin (CMC-544)
    • CD22 expressed in more than 90% of B cell NHLs
    • Not expressed on lymphocyte precursor cells and memory cells
    • CD22 internalized after antibody binding
    • Intracellular hydrolysis of the linker and release of calichemaicin: CYTOTOXIC
  • Inotuzumab Ozogamicin (CMC-544)
    • Potent cytotoxic in vitro and in vivo, also in Rituximab resistant tumors
    • Increased activity in xenograft models in combination with other agents (rituximab)
    • First phase I single agent study published in JCO, Advani et al April 2010
    Advani et al, JCO April 2010 )
  • Inotuzumab Ozogamicin (CMC-544) phase I study
  • Inotuzumab Ozogamicin (CMC-544) phase I study
    • RP2D 1.8mg/sm q4 weeks
    • Toxicities: Thrombocytopenia (60% gr 3-4 at the MTD), neutropenia (34.7%) asthenia (8.2%), nausea (2%)
    • ORR 39% (median number of previous treatments was 4, prior ASCT 18%). ( 68% in FL and 15% in DLBCL at the MTD)
    • Several ongoing studies in combination with rituximab
    • n=59, n=50 FL, n=5 MZL, n=3 FL
    • 3 previous lines, 54% high FLIPI
    • CMC-544 1.8mg/sm d1 q28 d
    Goy , ICML 201 1 # 068 ( Oral Presentation ) Phase II study of CMC-544 in pts with R/R iNHL (R to rituximab, R-chemo, RIT) AEs: PLT 67%, ANC:52%, Increased AST: 47% ORR CR All cases 55 % FL 62 % 10 pts 12 m PFS 50%
  • MoAbs targeting other antigens I HL, ALCL, T cell Human 30 MDX-060 80 30 30 30 40 40 CD I HL, ALCL 2nd generation, Fc engineered XmAb2513 Follicular HL, ALCL HL, CD30 NHL FL, Indolent CLL, FL, DLBCL Population II immunomodulatory effects Galiximab I/II Conjugated to MMAE (antitubulin agent) Brentuximab Vedotin (SGN-35) I Chimeric SGN-30 III IgG1, fully human Lucatumumab (HCD122) III IgG1 humanized Dacetuzumab Phase Specificity Agent
  • Brenduximab Vedotin(SGN35) Anti-CD30 conjugated to an antitubulin agent
  • Brentuximab Vedotin (SGN-35)
    • Antitubulin agent monomethyl auristatin E (MMAE) attached to a CD30-MoAb
    • Phase I study in 45 relapsed HL and ALCL patients (73% had a previous transplant)
    • MTD 1.8mg/kg q3w
    • AEs: fatigue, pyrexia, diarrhea, nausea, neutropenia, and peripheral neuropathy
    • 11 CR. Half of the patients at the MTD responded
    • Tumor regression in 86% of patients
    Younes A et al. N Engl J Med. 2010 Nov 4;363(19):1812-21
  • Phase II trial in RR HL
  • Patient Characteristics
  • Impressive response rate
  • Almost all patients had tumor reductions
  • Toxicities
  • Toxicities (cont)
  • Conclusions
    • n=102 pts with R/R HL, all had failed ASCT
    • SGN35 1.8mg/sm q21d (outpatient, over 30min, no premedication needed) up to 16 cycles
    • 31-ys, median 3,5 previous lines of chemo
    • follow-up 9m, duration of CR not reached
    Younes A et al , ICML 201 1 # 161 Durable complete remissions in phase II in R/R HL Peripheral neuropathy 47% (gr3 8%), ANC gr3(14%) 34% CR ORR SD All cases 75% 22%
  • MoAbs - Future directions
    • New anti-CD20 MoAbs in developmet to overcome resistance to rituximab
    • Good preclinical rationale (ofatumumab, GA101) but a superiority to Rituximab needs to be proved clinically
    • MoAbs against other antigens might be more effective in combination with rituximab or chemo
    • IV rituximab might be replaced by SC
    • Inotuzumab and Brenduximab are active and need to find a place in standard treatment
  • Small molecules inhibitors of oncogenic pathways
  • Proteosome inhibition
    • The proteosome regulates protein homeostasis
    • Inhibition of preotosome alters the cellular content of a variety of cell cycle and survival proteins (p53, NFkB,cdk)
    • Cell cycle arrest and apoptosis
  • Proteosome inhibition
    • Bortezomib
      • ORR of 25-50% in relapsed/refractory MCL
      • Modest activity in other lymphoma types
      • Activity in ABC DLBCL when combined with chemo
  • Weekly Bortezomib in combination with Rituximab in R/R iNHL and MCL
    • Italy, phase II BRIL06 trial of IIL
    • Number of prior Rx  2 = 77%
    • Rituximab pre-treated = 69%
    Chiapella, ASH 2010 # 3965 (Poster) Group Number Outcome MCL 25 ORR 64% MZL 8 ORR 50% SLL 16 ORR 37% All cases 49 ORR 53% All cases 49 PFS 2 25% All cases 49 OS 2 80%
  • Bortezomib + RCHOP in DLBCL and MCL Ruan et al, JCO,29 (690-7), 2011
    • phase I/II study in pts with untreated DLBCL (n=40) and MCL (n=36)
    • RCHOPq21, Bortezomib 0.7, 1 and 1.3mg/sm on d1 and d4
    • for DLBCL ORR 100%, 86% CR/CRu, 2y-PFS 64%, 2y-OS, for MCL ORR 91%, 72% CR/CRu, 2y-PFS 44%, 2y-OS 86%
    • in DLBCL similar outcomes for GCB and non-GCB (constitutive activation of NFkB in non-GCB may be the key)
  • Proteosome inhibition Future directions
    • Clinical evaluation in other lymphoma subtypes (also in T-cell lymphomas)
    • New combinations, especially with HDACi
    • New generation preteosome inhibitors
    • (oral, less neurotoxic)
  • Hystone deacetylase inhibitors
    • Promising targets because they regulate several pathways
    • Several compounds in clinical development
    • Activity in T cell cutaneous lymphomas
    • May increase the activity of other agents
  • Hystone deacetylase inhibitors
    • pan-HDACi (vorinostat, romidepsin, panobinostat) or class I HDACi (mocetinostat, etinostat)
    • Vorinostat and Romidepsin approved for CTCL (RR 30% in relapsed patients)
    • Limited single agent activity in DLBCL
    • Significant single agent activity in R/R HL (Panobinostat 20% RR, Mocetinostat)
  • Mocetinostat (MGCD0103) in R/R HL
    • USA, multicenter
    • Mocetinostat, an oral drug, given 3 times a week
    • 51 Cases, all had prior Rx including transplantation
      • Initial dose 85mg, n=28
      • Initial dose 110mg, n=23
    Younes, ASH 2010 # 1763 (Poster) Outcome 85mg (n=28) 110mg (n=23) Total (n=51) CR - 2 (8.7%) 2 (3.9%) PR 6 (21.4%) 6 (26.1%) 12 (23.5%) Durable SD 1 (3.6%) - 1 (20%)
    • MDA
    • Panobinostat 10  30mg (12 days in a cycle)
    • Everolimus 5  10mg (28 days in a cycle)
    Younes, ASH 2010 # 3664 (Poster) Phase I/II Study of Panobinostat + Everolimus in RR HL and NHL Histology Number Some kind of response HL 7 Yes T-Cell 3 Yes MCL 2 Yes DLBCL 2 No FL 2 Yes HL / DLBCL 1 No SLL 1 Yes
  • HDACi Future directions
    • Combinations with other active agents
      • demethylating agents
      • rituximab
      • proteosome inhibitors
      • chemotherapy
  • Targeting the PI3K/Akt/mTOR pathway
    • The PI3K/AKT/mTOR pathway receives signals from several receptors
    • regulates cell growth, proliferation, angiogenesis and cell survival
    • It is active in several lymphoma cell lines
    constitutive receptor activation survival factors
  • Temsirolimus (CCI-779)
    • Specific inhibitor of the mammalian target of rapamycin (mTOR)
    • Prevents progression from the G1 phase to S phase- CYTOSTATIC
    • Phase I study in 2004, Raymond et al: no MTD reached up to 220mg/sm weekly (gr1-2 euphoria followed by deppression in 3 pts)
  • Temsirolimus (CCI-779) experience in NHLs * 175x3w/75qw vs 175x3w/25qw vs investigators choise III II II II phase 162 72 29 35 n pts 2 2 4 3 previous lines * 25qw 25qw 250qw Dose 22 vs 6 vs 2 35% 41% 38% RR 89 vs 80 vs 68 nr Tc 39% Tc 65% AE gr3-4 MCL non MCL NHL MCL MCL Lymphoma type Author Witzig JCO 2005 Ansell Cancer 2008 Smith ab ASCO 2008 Hess JCO 2009
  • Single Agent Everolimus (RAD001) in R/R MCL
    • SAKK 36/06
    • Relapsed  3 prior lines of therapy or refractory MCL, 36 cases  evaluable 35
    • Everolimus 10mg/day, 1-28, 6 cycles
    • ORR  20%
    • CR  2 (6%), PR  5 (14%)
    • Median TTP (all cases) = 5.45 months
    Renner, ASH 2010 # 2803 (Poster)
  • Everolimus
    • RR 50% in FL, 30% in DLBCL,18% SLL, 53% in HL, 63% in PTCL
    • Maintenance therapy
      • Phase III study in DLBCL
      • Everolimus 10mg die vs placebo for 1 year
      • Patients in CR after RCHOP or similar
  • PI3K inhibitos
    • Targeting molecules upstream of mTOR might be more active
    • Three PI3K classes have been identified, but class I has been looked as anticancer target
  • PI3K δ isoform has a major role in B-cell survivall
    • Highly expressed in lymphoma cells
    • Constitutive activation and invoked PI3K activation are p110 δ -dependent in cell lines and primary patient cells
    • Microenvironment survival factors that are important in the development and maintenance of disease are p110 δ -dependent
  • High expression in several NHL lines
  • CAL-101, an oral PI3K δ inhibitor
  • Target inhibition in different lymphoma cell lines
  • Phase I study in R/R NHLs (indolent and aggressive)
  • Dose escalation
  • Adverse events
  • Reversible increase of liver enzymes
  • Clinical activity
  • Clinical activity (cont)
  • Phase I study in R/R NHLs (indolent and aggressive)
    • CAL-101, OD or BID 50mg BID to 350mg BID
    • n=30 iNHL, n=21 MCL, 4 previous lines, 455 refractory
    • RP2D 150mg BID
    • gr3+ AEs; increased AST/ALT (27%), anorexia (10%), pneumonia (10%), diarrea 88%), ANC (8%)
    Kahl B et al, 11-ICML, # 350 Outcome iNHL MCL CR 63% 48% PFS > 12m 4m
  • Immunomodulators
    • Anticancer drugs derived from Thalidomide (less toxic)
    • Exact mechanism of action remains unknown (direct antiproliferative effect, tumor microenvironment, angiogenesis, immune cell function)
    • Phase II trials of Lenalidomide showed promising activity in different lymphoma types (FL, DLBCL, MCL, T cell lymphomas)
  • Reduces Tumor burden Lenalidomide mechanism of action Activates T, NK and NKT cells NK and Tcell- mediated tumor killing Increases antigen presenting properties of tumor cells Arrests cell cycle Induces tumor suppressor genes Tumor cell apoptosis Activates caspases Disrupts stromal cell support Enhances Immunological synapse formation
  • Lenalidomide in R/R HL
    • Germany, GHSG
    • 45 Cases  evaluable 31
    • Lenalidomide 25mg/day, days 1-21, every 28 days, median 4 cycles
    Böll, ASH 2010 # 2828 (Poster) Outcome Figures CR 3% PR 25% SD 39% MR 10% PD 23%
  • Lenalidomide + R front-line therapy in iNHL
    • 76 pts , FL n=41, CLL/SLL n=15, MZL n=19
    • R d1, Lenalidomide 2 0 mg d 1-21, q28
    • ORR: 90%, CR 66% (87% in FL)
    • At study entry: 80% of FL had FLIPI ≥2 and 54% had high tumor burden
    • At a median fu of 14 months, only 4 pts had PD
    • After cycle 6, bcl-2 was no detectable in FL pts
    Fowler , ICML 201 1 # 137 ( Oral Presentation )
  • Other small molecules in clinical development Marginal activity in DLBCL Bifunctional inhibitor of apoptosis Survivin YM155 Agent Target Comments Results / Ongoing trials ABT-263 Bcl2 Targeting apoptosis RR 11% in SLL/CLL SB-1518 JAK2 JAK inhibitors Some responses in MCL, FL and HL Enzastaurin PKC Protein kinase C inhibitor In phase II, some activity in DLBCL and MCL Fostamatinib SYK SYK (TK) inhibitor 25%RR in DLBCL 50% in CLL PCI32765 Btk BTK inhibitor Phase I study Flavopiridol CDK CDK inhibitor 10% RR in DLBCL in phase I/II study
  • New agents for T cell lymphomas combinations with HDACi or demethylating agents RR 67% in RR PTCL and CTCL RR 61% first line with CHOP in PTCL and NK Proteosome Bortezomib Agent Target Results Ongoing trials Everolimus mTOR RR 63% in RR PTCL and CTCL combination with CHOP in first line Fosfamatinib disodium SYK na RR PTCL Vorinostat HDAC FDA approved for RR CTCL combination with CHOP in first line in PTCL Denileukin Diftitox IL2-R FDA approved for CD25+ RR PTCL in vivo purging with HD chemo and ASCT Zanolimumab CD4 na RR CTCL Brenduximab Vedotin CD30 R/R CD30+ ALCL combination with CHOP in first line
  • Considerations for future drug development
    • Clinical drug development proceeds through well established phases (I,II,III) but this may not be the case in NHL
    • Most of the recently approved drugs based on small phase II trials (no OS benefit)
    • What is considered active in phase II trials?
      • usually RR of 40-50% in R/R patients
  • How do we move forward
    • Preclinical problem
      • How do we choose the correct target
    • Clinical problem
      • Methods of early clinical development and priorities in phase I studies
      • Efficacy evaluation in phase II/III studies
  • Target identification
    • Better understanding of the molecular biology with identification of driver molecular defects of oncogenic pathways
    • Discover predictive biomarkers of response (CD20 + lymphomas do not necessarily respond to CD 20 MoAbs, ecc..)
    • Better preclinical models for the in vivo evaluation of new agents
  • Modern phase I studies
    • Establish the recommended phase II dose
    • Implemet pharmacodynamic endpoints (the highest dose is not always the most active)
    • Patient selection based on predictive factors of response
  • Efficacy evaluation
    • Most of the new agents have been approved based on results of small phase II studies
    • Problem of conflicting phase III trials of first line treatment
    • New trials design might be necessary
    • (eg randomized phase II trials)
    • Increase enrollment of patients in clinical trials and major collaborative efforts
  • Conclusions
    • Hundreds of new agents in development
    • Among both MoAbs and small molecules, there are several agents with clear activity in phase I and II studies in HL and NHL
    • The incorporation of these agents into standard care depends on the results of efficacy evaluation (in phase II and III trials)
    • We should make it a priority including patients in clinical trials that respond to relevant questions