The evolution of monoclonal antibodies in cancer medicine

Transcription

1 The evolution of monoclonal antibodies in cancer medicine Francisco J Hernandez-Ilizaliturri MD Professor of Medicine Chief Lymphoma and Myeloma Section Associate Professor of Immunology Departments of Medicine and Immunology Roswell Park Cancer Institute

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3 Does combined rituximab/chemotherapy improve overall survival in the treatment of patients with indolent Lymphoma? Schulz, H et al. Blood 106; 2005:351a

4 Number of therapeutic mabs entering clinical study per year ( ) There are currently >22 mabs approved by the FDA By 2008 engineered mabs are predicted to be account for more than 30% of the revenues in the biotechnology market Holliger P. et al. Nature Biotechnology 2005; 23:

5 Monoclonal antibodies: the story of a discovery that revolutionized science and medicine César Milst Georges Köhler and Niels Jerne Nobel Prize in Physiology or Medicine 1984.

6 A schematic representation of hydridoma technology Spleen cells from an immunized mice are fused, using polyethylene glycol, with myeloma cells that were rendered drug sensitive by a mutation in a growth essential gene hypoxanthine-guaninephosphoribosyl transferase (HGPRT). The cell mixture is then cultured in a medium containing the selective drug. As immune cells, although not sensitive to HGPRT, survive for only about one week in culture and the myeloma cells are drug sensitive they will all die within a week or so. The only cells that can survive are those hybrid myeloma cells that obtained a normal HGPRT gene from the immune cells. These hybridomas can grow continuously in vitro and some secrete antibody. By using appropriate screening technology, clones of cells that secrete antibody of interest can be identified and expanded in vitro or in vivo to obtain large quantities of monoclonal antibody that can subsequently be purified to homogeneity. Köhler G and Milst C. Nature 1975; 256:

7 The Evolution of mabs in Clinical Medicine Lonberg N. Nature Biothecnology 2005; 23: 1117.

8 Therapeutic antibody technologies Carter P. Nature Cancer Reviews 2001; 1: 118

9 Scott A. et all. Nature Reviews Cancer 2012; 12,

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11 B-Cell Marker B-cell receptor (BCR) CD19 CD20 CD21 CD22 CD23 CD38 Antigen (target) expression variable Most involved in B-cell growth, differentiation, proliferation, and activation CD40 CD52 CD46, CD55, CD59 CD74 Many are targets for treatment of B-cell cancers CD80

12 CD20 Expressed: Exclusively on B-cells Stable on B-cell surface, allowing sustained MAb binding B-Cell Function not well understood but believed to contribute to B-cell growth, proliferation, differentiation, and activation

13 Small Loop Large Loop 2 extracellular loops to which monoclonal antibodies may bind 1,2 MAb binding sites are near cell membrane, facilitating recruitment of cytotoxic effectors, both cells and proteins, to the B-cell surface 1,2 B-Cell Membrane 1 Cragg MS, et al. Curr Dir Autoimmun. 2005;8: Glennie MJ, et al. Mol Immunol. 2007;44(16):

14 ALL CLL, PLL Burkitt s, FL, DLCL, HCL WM MM Stem cell Pre-B Early B Intermediate B Mature B Plasmacytoid B Plasma ±CD5 CD19 CD20 CD22 CD52???

15 Complement-dependent cytotoxicity (CDC) 1-3 Antibody-dependent cellular cytotoxicity (ADCC) 1-3 Programmed cell death (apoptosis) Bello C, Sotomayor EM. Hematology Am Soc Hematol Educ Program. 2007;2007: Glennie MJ, et al. Mol Immunol. 2007;44(16): Jazirehi AR, Bonavida B. Oncogene. 2005;24(13):

16 CDC 1 Bhole D, Stahl GL. Crit Care Med. 2003;31(suppl 1):S97-S Shernan SK. Anesthesiol Clin North America. 2003;21(3): Shernan SK, Collard CD. BioDrugs. 2001;15(9):

17 ADCC Fc region of CD20-bound MAb binds to Fc receptor (FcR) on phagocytic cells, eg, natural killer cells, macrophages, neutrophils 1-3 Effector cells release mediators that damage and destroy B-cells 1-3 B-cells are phagocytosed Cragg MS, et al. Curr Dir Autoimmun. 2005;8: Glennie MJ, et al. Mol Immunol. 2007;44(16): Jazirehi AR, Bonavida B. Oncogene. 2005;24(13):

18 Apoptosis MAb binding to CD20 may induce transmission of intracellular signals that trigger cell cycle arrest and programmed cell death 1,2 Death Signal 1 Cragg MS, et al. Curr Dir Autoimmun. 2005;8: Glennie MJ, et al. Mol Immunol. 2007;44(16):

19 Examples of antibody-mediated signaling inhibition (a) Binding of ligand to a growth factor receptor triggers a dimerization event and activation of a signaling cascade, leading to cellular proliferation and resistance to cytotoxic agents (a). (b,c) MAb-based signaling inhibition can occur by blocking the dimerization event (b) or by interfering with ligand binding (c). Adams G et al. Nature Biothecnology 2005; 23: 1147.

20 Human antibodies, particularly IgG1 and IgG3, can potentially direct the killing of tumour cells by ADCC or CDC ADCC is triggered by an interaction between the Fc region of an antibody that has bound, through its antigenbinding region, to a tumour cell and the Fc receptors (Fc Rs), particularly Fc RI and Fc RIII, on immune effector cells such as neutrophils, macrophages and natural killer cells. Carter P. Nature Cancer Reviews 2001; 1: 118 Clynes et al. Nat Med 2000; 6:443-6 Hernandez-Ilizaliturri et al Clin Can Res 2003; 9: Hernandez-Ilizaliturri et al. Leu & Lymphoma, 2006; A prerequisite first step for CDC is recruitment of the complement component C1q by IgG bound to the tumour cell surface. Tumourcell-bound C1q can bind to complement receptors, such as C1qR, CR1 (CD35) and CR3 (CD11b/CD18), on effector cells, such as neutrophils, macrophages and natural killer cells.

21 Rituximab and Trastuzumab activity is mediated by ADCC Recruitment of natural killer (NK) cells,macrophages/monocytes, and PMNs by rituximab is via binding to their Fc γ receptors By increasing the number and/or activation state of effector cells,mab-associated cytotoxicity may be increased Clynes et al. Nat Med 2000; 6:443-6

22 Standard schedule Extended schedule Cartron G et al, Blood, 2002; 99: Ghielmini M. et al. Blood 2004; 104:588a

23 Mechanism of Action of Preoperative Trastuzumab in Patients HER2 + Breast Cancer Gennari et al. Clin Can Res. 2004: 10,

24 Mechanism of Action of Preoperative Trastuzumab in Patients HER2 + Breast Cancer Gennari et al. Clin Can Res. 2004: 10,

25 Novel strategies to improve the antitumor activity of Monoclonal antibodies

26 Transgenic mice producing human mabs Weiner L. J Immunother 2006; 29:1-9

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28 Sehn L. al. ASH 2011: 269

29 1. R-refractory Show single-agent activity (Phase II) Show efficacy in combination with chemotherapy or other active agents (Phase II) Show single-agent activity (Phase II) 2. R-sensitive (Untreated and Relapsed) Show efficacy in combination with chemotherapy or other active agents (Phase II) Show increased efficacy in a head-to-head study vs. rituximab (Phase III)

30 Number of Patients (%) (n = 116) Overall Response Rate 11% By dose cohort 500 mg (n = 30) 1000 mg (n = 86) By prior rituximab therapy Monotherapy (n = 27) Maintenance therapy (n = 45) R-chemotherapy (n = 44) 13% 10% 22% 9% 7% Median PFS 6.0 months Grade 3/4 AEs Neutropenia 17 (15%) Leukopenia 12 (10%) Thrombocytopenia 3( 3%) Cough 2 (2%) Infections 2 (2%) Hagenbeek et al. ASH 2009; abstract 935

31 IgG Fc receptor, FcγRIIIa Valine/Valine (V/V) and FcγRIIa Histidine/Histidine (H/H) genotypes predicted the response to rituximab in follicular lymphoma patients probably due to their higher affinity to the constant region (Fc) receptors Therefore, it may be possible to re-engineer the Fc of rituximab to increase its affinity to FcγR and thereby to enhance the antibody's ability to mediate ADCC and to improve its clinical efficacy. Similar observations were observed by another group of investigators using another anti-cd20 mab with higher CD16 affinity (AME- 133) Weng W. et. al. Blood 2005; 106:347a Weiner G. et. al. Blood 2005; 106:348

32 Patient characteristics (n = 22): Median age: 60 years (range, years) FL: 10; DLBCL: 3; CLL: 5 Stage III/IV disease: 15 (89%) Median prior therapies: 4 (range, 1-7); Half of the pts were R-refractory Maintenance Rx was permitted Number of Patients (%) (n = 22) Response to Induction Therapy ORR 5 PRs (23%) Stable disease 13 (59%) Grade 3/4 Toxicities Infusion-related reactions 4 Headache 1 Neutropenia 4 Febrile neutropenia 1 Infections (all grades) 6 A phase II trial of GA101 vs rituximab in relapsed indolent NHL is ongoing Sehn et al. ASH 2009; abstract 934

33 The role of FcγRIIIa genotype and effector cells in the biological responses to Rituximab Cumulative Survival Control Rituximab (Neutrophils present)* Rituximab (Neutrophils depleted)* Survival in Days P= Cumulative Survival 100 *Animals were also NK celldepleted Rituximab/NK & Neutrophils Rituximab/NK cells Placebo/NK cells Placebo/NK & Neutrophils Survival in Days P< Cartron G et al, Blood, 2002; 99: Ghielmini M. et al. Blood 2004; 104:588a Hernandez-Ilizaliturri et al Clin Can Res, 2003; 9:

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35 Cumulative Survival *P= Pom* + rituximab Cumulative Survival *P=0.167 Len* + rituximab 0.2 Pom 0.2 Rituximab* Len Rituximab* Placebo Placebo Time to Development of Limb Paralysis (days) Time to Development of Limb Paralysis (days) Hernandez-Ilizaliturri FJ, et al. Clin Can Res 2005;11:

36 NK Cell Day +10 Bars show mean Error bars show mean ± 1.0 SE Placebo CC4047 CC5013 Cumulative Survival Rituximab* CC rituximab* Placebo CC Time to Development of Limb Paralysis (days) *P=0.426 (n=40) Reddy N, et. al. Proc Am Soc Clin Oncol 2004;23:177 (Abstract 2556)

37 Patient Population Treatment Lenalidomide Rituximab TLS prophylaxis Response ORR CR/CRu Safety Rash Lymphopenia Neutropenia Myalgia Hyponatremia Fatigue Dutia et al n = 16 Relapsed/Refractory 25 mg/day, d1-21, q 28d 375 mg/m 2 /week, beg. d15 X 4 Allopurinol 12 (75%) 5 (31%) NR 4 (25%) 3 (18%) NR 3 (18%) 2 (12%) Fowler et al. n = 48/ 30FL Previously untreated (FLIPI Intermediate 60%/High 27%) 20 mg/day (10mg/d for SLL), d1-21, q 28d 375 mg/m 2, beg. day 1 X 6 None 89% (93% for FL) 73% (86% fir FL) 6 NR 7 4 NR 1 Dutia et al. ASH 2009; abstract 1679 Fowler et al. ASCO 2010; abstract 8036

38 Clinical responses SD SD PR CRu PR CRu CR CR After 3 cycles After 6 cycles PCR results * Screening S/P cycle 3 S/P cycle 6 BCL-2 (+) BCL-2 (-) Total % conversion Molecular responses - 8/11 (73%) 10/11 (91%) *Bone marrow and peripheral blood were tested at baseline, cycle 3 and cycle 6. The PFS at 20 months is 91% Fowler et al. ASCO 2010; abstract 8036

39 Drug Dose Administration Rituximab 375 mg/m 2 IV Day 1/28 x6 cycles; if clinical benefit, can give 12 cycles Lenalidomide 20 mg/day* PO Days 1-21/28 x6 cycles; if clinical benefit, can give 12 cycles Phase II, open label, single arm, single institution study Primary endpoint: ORR; Secondary: PFS, OS, Safety Designed to enroll 110 patients in 3 cohorts: 50 FL (grade I/II), 30 MZL, 30 SLL/CLL Restaging was performed after cycles 3 and 6 Lenalidomide increased to 25 mg/day after 3 cycles if SD *SLL patients received 10 mg/day cycle 1, 15 mg/day cycle 2, 20 mg/day on cycle 3. Samaniego et al, ASCO 2011, Abstract 8030 Fowler et al. ICML 2011, Abstract 137 Cheson et al. J Clin Oncol. 1999;17:

40 Patient Characteristics, n (%) (N = 100) Median Age (range) Histology FLIPI Score (N = 49) 58 years (34 84 years) Marginal Zone 27 (27) SLL 24 (24) Follicular 49 (49) Low 10 (20) Intermediate 25 (51) High 14 (29) *GELF Criteria: 3 nodes > 3 cm or 1 greater than 7cm Systemic/local symptoms from disease Compression/risk of compression of vital organ Cytopenia due to marrow infiltration Splenomegaly > 16cm GELF Criteria for High Tumor Burden* 50 (50) Bulky Disease (mass > 7 cm, or 3 nodes > 3 cm) 22 (22) Stage III/IV 100 (100) LDH (31) Samaniego et al, ASCO 2011, Abstract 8030 Fowler et al. ICML 2011, Abstract 137

41 Response by Histology, n (%) N ORR (Evaluable) CR/CRu PR SD FL (98) 38 (85) 6 (13) 1 (2) SLL (83) 6 (25) 14 (59) 2 (8) MZL (88) 16 (67) 5 (21) 3 (14) Total (91) 60 (51) 25 (27) 6 (6) Response in FL by Tumor Burden, n (%) N ORR CR/CRu PR SD GELF + High tumor burden (95) 1 (5) 0 GELF High tumor burden (78) 4 (17) 1 (5) Bulky (92) 1 (8) 0 Non-Bulky (84) 4 (13) 1 (3) Response in FL by PCR, n (%) N Positive Negative Pretreatment (40) 26 (60) Post Cycle (12) 38 (88) Post Cycle (5) 40 (95) Samaniego et al, ASCO 2011, Abstract 8030 Fowler et al. ICML 2011, Abstract 137

42 All Evaluable Patients Follicular Lymphoma Samaniego et al, ASCO 2011, Abstract 8030 Fowler et al. ICML 2011, Abstract 137

43 CD20+ FL relapsing after rituximabchemotherapy treatment Rituximab weekly x 4 Lenalidomide on days 1 21 q28 days x 12 cycles Rituximab weekly x 4 + lenalidomide on days 1 21 q28 days x 12 cycles Peripheral blood for: FcγR-III polymorphisms, changes in NK cells, activated NK cells, activated T-cells, changes in cytokine production CALGB 10002: Primary endpoints: ORR, CR and TTP

44 On-Going lenalidomide Lymphoma Registration Study In FL GELA FL-001* Phase III randomized study of lenalidomide vs R-Chemo in 1 st -line FL patients

45 Rituximab & CMC544+*^ CMC544* Rituximab^ Placebo+ N = 60 Advani A, et al Blood 2005, 106:230a Hernandez-Ilizaliturri F, et al Blood 2005, 106:230a

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47 Antibody-directed enzyme prodrug therapy (ADEPT) The cytotoxic agent is administered in an inactive (prodrug) form The mab-enzyme conjugate Adams G et al. Nature Biothecnology 2005; 23: 1147.

48 Antibody-targeted Radiation Cancer Therapy Milenic D et al. Nature Reviews Drug Discovery 2004; 3: 489.

49 The Choice of the Radioisotope Milenic D et al. Nature Reviews Drug Discovery 2004; 3: 489.

50 Pre-targeted radiotherapy Sharkey, R. M. et al. Clin Cancer Res 2005;11:7109s-7121s

51 Engineered antibody fragments and the raise of single domains Holliger P et al. Nature Biothecnology 2005; 23: 1126.

52 Engineered antibody fragments LS174T Colon Ca C6 Glioma Anti-Her2/neu abs Holliger P et al. Nature Biothecnology 2005; 23: Imaging 18 hrs after infusion of a 124I labeled anti-cea T84.66 diabody, minibody or scfv-fc

53 Can mab trigger adaptive immune responses? Galiximab, ipilimumab Dominant interaction APC T-cell CTLA-4 expression and T-cell activation CD80 Dominant interaction CD86 CD28 CD152 APC Galiximab biding to CD80 T-cell Inactivation of CD28 mediated signaling, i.e. T-cell inactivation APC T-cell Inactivation of the negative interaction between CD152 and CD80 leading to T-cell activation

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55 Clinical Activity in Nivolumab (human anti-pd-1 IgG4) -Treated Patients

56 Nivolumab vs. Docetaxel in stage IV NSCLC (squamous cell subtype)

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