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PPB 2009 Presentation Sym001 Rozrolimupab for treatment of Immune Thrombocytopenic Purpura (ITP) and Anti-D Prophylaxis (ADP) The Sixth Plasma Product Biotechnology Meeting Torben P. Frandsen, Director of Antibody Chemistry Symphogen A/S 3rd generation of therapeutic antibodies Immunoglobulins Recombinant polyclonal antibody products Diverse: + Specific: ÷ Diverse: + Specific: + Monoclonal antibodies Diverse: ÷ Specific: + Proprietary antibody technologies 18 MonthstoPreclnical Development Symplex™ Discovery engine • Human antibody drug lead candidates – Natural VH-VL pairing preserved – Natural high affinities and reactivities http://www.symphogen.com/web/guest/symplex Sympress™ Expression engine • Recombinant polyclonal Ab products • Single batch manufacturing • Batch-to-batch consistency • Industrial scale http://www.symphogen.com/web/guest/sympress Symphogen product pipeline Sym001 rozrolimupab Indications ITP: Treatment of Immune Thrombocytopenic Purpura ADP: Anti-D prophylaxis to prevent Hemolytic Disease in Newborns (HDN) Target Rhesus D on Red Blood Cells Opportunity Replacement of blood-derived immune globulin products (IVIG and Anti-D) Class Recombinant polyclonal antibody product (pAb) Composition 25 human full-length IgG1 Abs with documented RhD reactivity Stage ITP: Phase 2 ADP: Phase 1/2, RBC challenge in healthy volunteers Sym001 product characteristics • Sym001 antibody leads identified from Danish anti-D donors by phage display technology • Sym001 comprises 25 unique human IgG1 antibodies • Sym001 comprises antibodies with verified reactivity against RhD III, RhDIV, RhDVI, RhDVII • Sym001 clones do not react with: ABO, E, f, P1, Lea, Leb, Lub, N, S, s, JKa, JKb, Fya, Fyb, K, k, Kpb, Rd, Vel, Ge, and H(0). • Sym001 mimicks the IgG repertiore of anti-D donors Sym001 mimics the IgG repertoire of anti-D donors B 80 A 100 90 70 80 60 ) 70 50 60 50 40 40 30 Frequency (%) Frequency 30 (% Frequency 20 20 10 10 0 0 V H1 V H2 V H3 V H4 V H5 V H6 V H7 VH-family IGVH3 allele C D 80 50 70 40 60 50 30 40 30 20 Frequency (%) Frequency 20 (%) Frequency 10 10 0 0 JH1 JH2 JH3 JH4 JH5 JH6 16 17 18 19 20 21 22 23 24 25 26 32 JH gene usage CDR3-H le ngth (A) frequencies of heavy chain V gene family (B), VH3 gene allelic usage (C), J gene segment usage and (D) CDR3 region length in amino acids. Sym001 (white bars) is compared to a compilation of the 165 known VH sequences of human anti-RhD antibodies (grey bars). Sym001 mediates erythrocyte destruction in vitro • Several MoA have been described for anti-D in RhD prophylaxis • Destruction of RhD+ erythrocytes is the most likely MoA; – Phagocytosis – Antibody-dependent cellular cytotoxicity (ADCC) • In vitro efficacy of Sym001 is similar to anti-D products for binding potency assays Sym001 blocks platelet uptake in macrophages • Anti-D MoA for inhibition of platelet destruction in ITP: – Anti-D opsonized RhD+ erythrocytes competes for FcγR at RES macrophages – Anti-D opsonized RhD+ erythrocytes induce refractory period in RES macrophages • Sym001 blocks platelet uptake in macrophages ITP model 120% Sym001-rWS1 WinRho 100% 80% 60% 40% % Platelet Phagocytosis 20% 0% 10 100 1000 10000 100000 Concentration of anti-D (ng/ml) Manufacturing, Release and Characterization of Recombinant Polyclonal Antibody Products SympressTM Technology Polyclonal antibody expression • Mammalian expression (CHO) • Site-specific integration (Flp-In system) • Single integration event per cell • Homogenous expression & growth • Identical constant regions Generation of the PALS cell lines • Identical sub-cloned parental cells • Identical plasmids, apart from the antibody genes • Transfection, adaptation and banking same for all PALS • Each cell produces only one antibody • PALS generation a one time event GMP cell banks and manufacturing process • The pMCB and pWCB are the GMP cell banks • Both are polyclonal cell banks • One vial of pWCB is thawed for each Sym001 DS batch Antibody characterization strategy Typical characterization of mAb Sym001 Structural integrity Structural integrity • Western blotting • Western blotting • Capillary electrophoresis • Capillary electrophoresis • Size exclusion chromatography • Size exclusion chromatography Analysis of variable & Analysis of constant region constant region • Peptide mapping • Disulphide bridges • Peptide mapping • Carbohydrate analysis • Disulphide bridges • Carbohydrate analysis Assessment of polyclonality • CIEX profiling • Identification of marker peptides by LC-MS Release and characterization assays Release assays Characterization assays • Identity • N-linked carbohydrate – Constant region • Primary structure – Sym001 specific • Secondary structure • Purity • Thermal stability – Product related • Product related contaminants – Process related • Biological characterization • Quantity • In vitro safety profiling • Potency • General Manufacturing of Sym001 Sym001 Cell bank Scale (L) Use Batch MYS05-01 pMCB 400 Experimental MYS05-02 pMCB 400 Toxicology studies MYS05-03 pMCB 400 GMP campaign for clinical phase 1 and 2 MYS05-04 pMCB 400 MYS08-01 pWCB (pWCB-02) 400 GMP campaign intended MYS08-02 pWCB (pWCB-02) 400 for future clinical studies MYS08-03 pWCB (pWCB-02) 400 Similar compositional diversity of Sym001 demonstrated in 4 manufacturing runs Working standard Tox batch GMP 1 batch GMP 2 batch CIEX profiling. Spiking with RhD mAb g( ) mAU Working standard RhD240 200 Working standard spiked with RhD240 RhD240 150 100 50 0 10 20 30 40 50 60 70 80 90 100 min CIEX profiling. Spiking with RhD mAb mAU RhD157 Working standard RhD157 200 Working standard spiked with RhD157 150 100 50 0 10 20 30 40 50 60 70 80 90 100 min CIEX profiling 319, (157) 319 293 293, 319 157, 192 157, 189, 199 159 191, 201, 241 189, 192, 199 191 160 160, 201 160 (306) (191), (201), (202), (305), (306) 162, (301) 202 245, 301, (305) 203 162 202 305, 321 197 196 197, 305 321 196, 324 197 321 196, 317 324, 317 317 207 207 207 240 240 Marker Peptide Method SaM16959 11 05061502:11_UV SaM16959 11 05061502:11_Fractions SaM16959 11 05061502:11_Inject mAU 500 400 300 200 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 1415 Waste 70.0 80.0 90.0 100.0 110.0 120.0 130.0 140.0 min Drug Substance HC/LC Separation Protease Digestion Ab Identification MS Analysis HPLC Separation Development of a marker peptide method The presence of all 25 antibodies have been confirmed in 4 scale-up batches Sym001 CMC development and characterization • Regulatory path for future approval of Sym001 established • Two-tier polyclonal cell bank concept established (pMCB/pWCB) to support manufacturing during product lifespan • Recombinant polyclonal antibodies can be reproducibly manufactured at industrial scale – 400 L scale – 12,500 L simulation • An extensive package of methods for release and characterization of recombinant polyclonal antibodies have been developed • Methods to control consistency have been developed Indications and clinical development Hemolytic Disease of the Newborn • 16% of caucasians lack RhD on their red blood cells (RhD-) • Annually there are 1.3 million live births to RhD- women in the US and Europe • HDN risk if a RhD- woman is pregnant with RhD+ RhD- fetus RhD+ – RhD+ fetal blood may leak to mother’s circulation causing a maternal immune response to RhD antigen (isoimmunization) • Future pregnancies – Mother’s immune response causes destruction of red blood cells in a RhD+ fetus and development of HDN • HDN – Fetal hemolysis and multi organ failure – Severe handicaps and death Immune Thrombocytopenic Purpura (ITP) Rare autoimmune disease resulting in platelet destruction • Children: Acute disease 2-3 weeks after viral infection. Spontaneous remission in 80% within 6 months Bruises and bleedings Platelets/mm3: • Adults: Chronic disease with < 30,000 Treatment < 20,000 Spontaneous insidious onset. Secondary to bleeding viral infections, drugs and <10,000 Epistaxi, hematuria malignancies bleedings from mucosa and skin < 5,000 Spontaneous • New ITP cases annually: internal bleedings 19,000 adults and 8,000 children (US and Europe) Sym001 – phase 1 • 7 dose cohorts Cohort 1 7 RhD+ subjects Cohort 2 7 RhD+ subjects Cohort 3A Cohort 3B 9 RhD+ subjects 9 RhD negative subjects Cohort 4A Cohort 4B 9 RhD+ subjects 9 RhD negative subjects Cohort 5 9 RhD+ subjects Cohort 6 9 RhD+ subjects Cohort 7 Hjelmstrøm et al. ASH 2008 9 RhD+ subjects Hemoglobin (mean change from baseline per cohort in RhD+ subjects) Hjelmstrøm et al. ASH 2008 Confidential /28 ADP: Proof of mechanism study • Sym001 given to 24 RhD- negative healthy males challenged with RhD+ RBCs i.v. • Positive control: Rhophylac® given to 12 RhD- negative healthy males challenged with RhD+ RBCs i.v. • Study objectives: – To assess the ability of Sym001 to eliminate RhD+ red blood cells in RhD- subjects – To assess suppression of RhD immunization • Preliminary results: Dose-dependent clearance of RhD+ RBCs established with Sym001 at five days (Press release 21 Nov 2008) ITP: Proof of concept Study • Initiated Jun ’08 (Press release 16 Jul 2008) • Phase 2 dose-escalation study • Objective: – To evaluate safety – To determine pre-liminary efficacy on platelet count • 23 sites in Europe Conclusions • Sym001 is expected to have same or better benefit/risk and coverage as blood-derived anti-D while offering recombinant benefits over IVIG and anti-D: – Safety, convenience, supply, drug consistency • Recombinant polyclonal antibodies can be reproducibly manufactured at industrial scale • Recombinant polyclonal antibodies are well characterized through an extensive package of methods for release and characterization • Clinical data shows good safety profile. POC data from phase 1 and phase 2 in RhD+ and RhD- subjects • Regulatory expectations mapped through close dialogue with authorities in US and Europe Acknowledgements • Sym001 is co-developed with Biovitrum • Numerous employees at Biovitrum & Symphogen • Contact: [email protected] • Thank you.
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