Aptevo Therapeutics Inc. · NASDAQ:APVO
Aptevo Therapeutics — BIO International Convention 2017
53 slides from Aptevo Therapeutics's conference presentation, Jun 20, 2017
Slide 1: Developing Next-Generation ADAPTIR Molecules From the Bench to the Clinic
Developing Next-Generation ADAPTIRTM Molecules From the Bench to the Clinic BIO International 19-21 June, 2017 Aptevo Therapeutics Exhibit 99.1
Slide 2: Agenda
Overview of ADAPTIR Bispecific Technology Bispecifics in Immuno-Oncology Next Generation ADAPTIR Candidates Portfolio of Preclinical Candidates ADAPTIR Lead Selection Process ADAPTIR Platform: Key CMC Advantages Summary Agenda
Slide 3: Overview of ADAPTIR Bispecific Technology
Overview of ADAPTIR Bispecific Technology
Slide 4: ADAPTIR – A Modular Technology
ADAPTIR – A Modular Technology Monospecific mAb Bispecific Targeted Cytokine Delivery Previously known as SMIP and SCORPION platforms
Slide 5: Overview of ADAPTIR Platform
Aptevo’s monospecific and bispecific antibody platform technology for novel immuno-oncology therapeutics Robust, flexible bispecific platform fit for different mechanisms of action T-cell engagers; redirected T-cell cytotoxicity (RTCC) Directed cytokine delivery Co-engagement of cell receptors or so
Slide 6: Unique Features of ADAPTIR Bispecific Platform Technology
Unique Features of ADAPTIR Bispecific Platform Technology Bispecific ADAPTIR Therapeutic Novel homodimer structure simplifies CHO production with increased manufacturing yields Single gene, ease of CHO cell line production Better yields and cost-of-goods than heterodimers Predictable manufacturabili
Slide 7: Unique Features of ADAPTIR Bispecific Platform Technology (continued)
Unique Features of ADAPTIR Bispecific Platform Technology (continued) scFv structures optimized to improve stability and manufacturability Antibody-like melting temperature Long-term stability Immunoglobulin hinge-Fc extends half-life, simplifies manufacturing 12.5 days demonstrated in rodents, NHP
Slide 8: ADAPTIR Bispecifics in Immuno-Oncology
ADAPTIR Bispecifics in Immuno-Oncology
Slide 9: Diversity of Opportunities to Boost Anti-Tumor Responses Using Bispecific Molecules
Diversity of Opportunities to Boost Anti-Tumor Responses Using Bispecific Molecules T cell Engager Tumor Lysis NK cell Engager Tumor cells Tumor Lysis T cell Tumor Lysis Prime response Reverse suppression Multiple Check-point Blockade CD3 T cell Macrophage DC
Slide 10: Versatility of Bispecific ADAPTIR Platform
Platform enables multiple modalities to stimulate T-cell function Stimulation of adaptive and innate cell responses Stimulation in trans or cis Engagement of TCR/CD3, costimulatory receptors or cytokine receptors Versatility of Bispecific ADAPTIR Platform T-cell CD3 engagers T-cell co-stimulators Ta
Slide 11: Unique Features of ADAPTIR Bispecific RTCC Candidates and Selection Process
Bispecific ADAPTIR Therapeutic Anti-tumor scFv Anti-CD3 scFv No ADCC/CDC * MOR209/ES414, A Novel Bispecific Antibody Targeting PSMA For The Treatment of Metastatic Castration-Resistant Prostate Cancer, Hernandez-Hoyos et al. Molecular Cancer Therapeutics, July 12 2016 DOI: 10.1158/1535-7163.MCT-15-0
Slide 12: ADAPTIR Induces More Potent RTCC than Monovalent Heterodimers
ADAPTIR RTCC molecules have been compared to 3 heterodimer formats targeting the same tumor antigen ADAPTIR More Potent Lower EC50 ADAPTIR Heterodimers examples * Unpublished in vitro preclinical studies * ADAPTIR: Bivalent Interaction with Target Induces more Potent RTCC than Monovalent Heterodimer
Slide 13: ADAPTIR RTCC Candidates Induce Lower Levels of Cytokines than Competitor scFv-scFv
ADAPTIR RTCC Candidates Induce Lower Levels of Cytokines than Competitor scFv-scFv 20 hr stimulation of T cells with ADAPTIR and tumor cells 3 representative cytokines shown out of 16 cytokines tested Compared ADAPTIR to scFc-scFv targeting same tumor antigen in 20 hr activation assay IL-2 15000 100
Slide 14: ADAPTIR RTCC Candidates Induce Robust Proliferation of T cells
Four-day proliferation of CD8 T cells in the presence of target cell T cells undergo multiple cells divisions and differentiate into effector memory cells ADAPTIR RTCC Candidates Induce Robust Proliferation of T cells CFSE 500 400 300 200 100 0 0 102 103 104 105 CFSE 76.6
Slide 15: Next Generation ADAPTIR Bispecifics Optimized Structure
Next generation ADAPTIR candidates have been optimized for Improved stability and improved manufacturability Improved half-life; 12.5 day half-life in rodents Removed potential sequences with risk to immunogenicity Next Generation ADAPTIR Bispecifics anti-tumor scFv aCD3 scFv Optimized ADAPTIR RTCC
Slide 16: Next Generation ADAPTIR RTCC Candidates Show Improved Immunogenicity Profile
Next Generation ADAPTIR RTCC Candidates Show Improved Immunogenicity Profile – Low ADA Risk T-cell assays performed on peptides derived from ADAPTIR RTCC platform and candidates IFN-gamma response measured for 20 donors with most common HLA alleles Low mean response observed in Next Generation ADAPT
Slide 17: ADAPTIR Portfolio of Candidates
ADAPTIR Portfolio of Candidates
Slide 18: ADAPTIR Monospecific / Bispecific Portfolio
Product Candidate Technology Indication Target Pre-Clinical Clinical Development Stage Milestones/Highlights Phase I Phase II Phase III Otlertuzumab ADAPTIR Monospecific CLL CD37 Executing Phase 1b combination study MOR209 ES414* ADAPTIR Bispecific RTCC mCRPC Immuno-oncology CD3/PSMA Executing Phase
Slide 19: Clinical Candidate – otlertuzumab (CLL)
Clinical Candidate – otlertuzumab (CLL) aCD37 scFv Human IgG1 Fc Humanized monospecific protein therapeutic Targets CD37 and its signaling pathway involved in B-cell malignancies Built on ADAPTIR (modular protein therapeutic) platform Demonstrated anti-tumor activity Prolonged serum half-life (mouse
Slide 20: Clinical Candidate – MOR209/ES414 (mCRPC)
Clinical Candidate – MOR209/ES414 (mCRPC) Anti-PSMA Anti-CD3 Humanized bispecific protein therapeutic Targets PSMA and CD3, a component of the T-cell receptor Demonstrated redirection of T-cells to kill tumor cells expressing PSMA in vitro and in vivo Prolonged serum half-life (mouse/NHP) vs antibod
Slide 21: ADAPTIR Preclinical Candidates
ADAPTIR Preclinical Candidates
Slide 22: ADAPTIR - Preclinical Pipeline
ADAPTIR - Preclinical Pipeline Molecule Target Antigen Type Target Indication(s) Development Activity Design in vitro RTCC in vivo POC IND-Enabling Clinical: Phase 1 aCD123 X aCD3 CD123 Hematologic malignancies aROR1 X aCD3 Tyrosine Kinase (ROR1) Hematologic malignancies; solid tumors Multiple RTCC
Slide 23: APVO436: CD123 x CD3 Bispecific ADAPTIR
APVO436: CD123 x CD3 Bispecific ADAPTIR Targets multiple hematological malignancies Acute myeloid leukemia, acute lymphoblastic leukemia, hairy cell leukemia, myelodysplastic syndrome, blastic plasmacytoid dendritic cell neoplasm Lead and back-up candidates identified with similar in vitro propertie
Slide 24: APVO436 Key In Vitro Data
Derived from a fully human anti-CD123 binding domain generated in humanized mice Binds human CD123-expressing cell lines and potently induces RTCC, T-cell activation and proliferation Activity is dependent upon the presence of CD123+ target cells Demonstrates good functional activity to cynomolgus C
Slide 25: APVO436 Has Antibody-Like Half-Life in Balb/c Mice
APVO436 Has Antibody-Like Half-Life in Balb/c Mice Half – life up to 12.5 days demonstrated in rodents Parameter APVO436 T 1/2 301 hours (12.5 days) Clearance 0.186 ml/hr/kg Volume 80.84 ml/kg AUC 37309 hr* µg/ml Concentration (μg/mL) Serum Concentration 1000 100 10 1 0 72 177 216 288 360 432 504 Ti
Slide 26: APVO436 Inhibits Tumor Growth in Xenograft Model of Human AML
APVO436 Inhibits Tumor Growth in Xenograft Model of Human AML Day 11: APVO436, 0.6 mg Group (Tumor + T cells) Day 11: Vehicle Control Group (Tumor + T cells) Growth of MOLM-13/LUC Cells (Bioluminescence Imaging) Bioluminescence Total Flux [p/s] 1010 019 108 107 106 0 2 4 6 8 10 12 Days post tum or c
Slide 27: APVO436 Prolongs Survival in Xenograft Model of Human AML
APVO436 Prolongs Survival in Xenograft Model of Human AML Treatment Group Median Survival Time (Days) Survival Relative to Molm-13 + T cells/Vehicle Control (P value) Molm-13 + T cells/Vehicle 17 (-) Molm-13 + T cells/APVO346 15 µg Undefined <0.0001 Molm-13 + T cells/APVO346 3 µg Undefined <0.0001 M
Slide 28: Antibody-like expression levels of APVO436 in CHO Production Cell Lines
Reproducible production of more than 1.5 g/L of APVO436 in 10-L cultures Antibody-like expression levels of APVO436 in CHO Production Cell Lines Titer (mg/mL) 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 8 10 12 14 Day
Slide 29: aROR1 x aCD3 ADAPTIR Pilot Candidate: Summary
aROR1 x aCD3 ADAPTIR Pilot Candidate: Summary aROR1 scFv aCD3 scFv ROR1 Tumor Antigen Modified Fc No ADCC or CDC Novel therapeutic that redirects T cells to kill ROR1-expressing tumor cells Active in in vitro and in vivo studies at very low concentrations Competitive with other bispecific antibody f
Slide 30: aROR1 x aCD3 Delays Tumor Growth and Improves Survival in a Xenograft Model
aROR1 x aCD3 Delays Tumor Growth and Improves Survival in a Xenograft Model Statistically significant delay of tumor growth in and increase in overall survival in MDA-MB-231 subcutaneous xenograft model 8/10 mice at top dose (3 mg x3) tumor free at end of study Tumor Volumes Mean Tumor Volume (mm3)
Slide 31: ADAPTIR Platform Lead Selection Process
ADAPTIR Platform Lead Selection Process
Slide 32: ADAPTIR Candidates are Screened to Meet Detailed Product Profile Criteria
Activity and affinity consistent with desired mechanism of action ADAPTIR Candidates are Screened to Meet Detailed Product Profile Criteria Function Stability In-vivo Suitability Stable under manufacturing, storage and dosing conditions Stable in serum, no off-target binding, low immunogenicity pote
Slide 33: Screening and Optimization of Stable scFvs Enables mAb-like Performance
scFv domains obtained from human phage library to leverage stable IgG frameworks, or humanized rodents to leverage high affinity human binding domains High throughput screening and characterization assays are performed in ADAPTIR format scFv must achieve Tm >60 °C without reliance on additional stab
Slide 34: ADAPTIR Bispecifics Utilize Modified Fc to Eliminate ADCC and CDC Function
Thermostability and FcRn binding similar to wt IgG1 Fc ADAPTIR Bispecifics Utilize Modified Fc to Eliminate ADCC and CDC Function Molecule IgG subtype Molecule Type KD by SPR (nM) scFv-Fc-scFv ADAPTIR IgG1 Fc (ADCC and CDC null) ADAPTIR bispecific 26 trastuzumab IgG1 WT MAb 64 etanercept IgG1 WT ECD
Slide 35: Standardized Approach for ADAPTIR Candidate Evaluation
Standardized Approach for ADAPTIR Candidate Evaluation scFvs are screened for functional, conformational and colloidal stability Category Assays Thermostability DSC (Tm) DSF (Tm, Tagg) Solubility High-salt solubility screen Protein concentration screen Process compatibility Process intermediate stab
Slide 36: ADAPTIR Candidates are Screened for Cleavage Susceptibility at Domain Junctions
ADAPTIR Candidates are Screened for Cleavage Susceptibility at Domain Junctions D6* T0 D1 D2 D3 D1 D2 D3 Construct “B” T0 Construct “A” New candidates are selected to be resistant to proteolytic cleavage to minimize degradation products during expression and in vivo use Eliminates need for specific
Slide 37: ADAPTIR Molecules Achieve both Functional and Stability Objectives
ADAPTIR Molecules Achieve both Functional and Stability Objectives Standardized process for identifying stable, active constructs Research, process, analytical and formulation development teams review data and select clinical lead construct ID %Protein Loss, Salt Spike Target Binding KD (nM) scFv Tm
Slide 38: ADAPTIR Molecules Are Stable Under Accelerated Stability Conditions
ADAPTIR Molecules Are Stable Under Accelerated Stability Conditions (40 °C) T=0: 0.21% HMW T=7days at 40oC; 1.9% HMW Careful selection of lead facilitates subsequent development and cGMP manufacturing Enables rapid progression of candidates to clinic 0.60 0.55 0.50 0.45 .040 0.35 0.30 0.25 .020 0.15
Slide 39: ADAPTIR Platform Key CMC Advantages
ADAPTIR Platform Key CMC Advantages
Slide 40: Proven PD and Manufacturing Platform
Proven PD and Manufacturing Platform 8 GMP lots across multiple molecules History of successful transfer to CMOs Experience Standard CHO cell line Titers > 1 g/L achieved for early-phase processes Successfully scaled to 2,000 L Standard commercially-available defined media Fed-batch processes with s
Slide 41: Proven PD and Manufacturing Platform
Proven PD and Manufacturing Platform 8 GMP lots across multiple molecules History of successful transfer to CMOs Experience Standard CHO cell line Titers > 1 g/L achieved for early-phase processes Successfully scaled to 2,000 L Standard commercially-available defined media Fed-batch processes with s
Slide 42: ADAPTIR Expression Levels Meet Clinical and Commercial Demands
ADAPTIR Expression Levels Meet Clinical and Commercial Demands Cell-culture titers are typically greater than 1 g/L prior to process optimization Cell-culture titers greater than 2 g/L have been achieved after process optimization ADAPTIR proteins are produced at levels that easily meet clinical & c
Slide 43: Deglycosylated ADAPTIR Proteins are Well-Characterized Protein Therapeutics
Deglycosylated ADAPTIR Proteins are Well-Characterized Protein Therapeutics Standard mAb-like analytical techniques are used for characterization and release testing LC-MS analyses of ADAPTIR candidates show: Proper disulfide bond formation Glycosylation pattern consistent with CHO-expressed mAbs Na
Slide 44: Rapid PD from Lead to Clinic in 18 months
Aptevo employs a process & analytical development platform enabling rapid transfer from research to clinical development Rapid PD from “Lead to Clinic” Clone Selected Upstream & Downstream Process Defined CMC Fully Defined Clinical Manufacturing Initiated 18 months Clone Candidates Lead to Clinic in
Slide 45: Highly Favorable Supply Economics
Highly Favorable Supply Economics Highly Active minimize drug quantities required Low COGs Robust Supply mAb-like manufacturing means excellent process fit and no special equipment 500 - 2000 L scale readily amenable to single-use technologies *In preclinical experiments
Slide 46: ADAPTIR Summary
ADAPTIR Summary
Slide 47: ADAPTIR Summary
ADAPTIR is Aptevo’s monospecific and bispecific antibody platform technology for generating novel immuno-oncology therapeutics ADAPTIR is a robust, flexible platform that can be used to generate bispecific molecules with different mechanisms of action ADAPTIR platform has distinct advantages over ot
Slide 48: Back-up
Back-up
Slide 49: APVO436 Binds CD123 and CD3 with High Affinity
APVO436 - ADAPTIR Lead Candidate Binds CD123 and CD3 with High Affinity Molm-13 (Human CD123) Jurkat (Human CD3) CHO Cyno CD123 2nM 2nM 7nM Ka (1/Ms) Kd (1/s) KD (nM) 1.6 x 105 3.7 x 104 2 Binding Affinity by Flow cytometry Binding Affinity to Human CD123 by SPR Affinity to human CD123 by Biacore Hu
Slide 50: APVO436 Induces Redirected T-Cell Cytotoxicity of CD123+ Tumors
APVO436 Induces Redirected T-Cell Cytotoxicity (RTCC) of CD123+ Tumors RTCC activity demonstrated using both Human and Cynomolgus T cells targeting Molm-3, a CD123+ tumor cell line Molm-13 (Hu T cells) Molm-13 (Cyno T cells) CHO/Cyno CD123 (Hu T cells) 4 pM 2 pM 3 pM EC50 values in RTCC assays Molm-
Slide 51: APVO436 Induces Target Dependent T-cell Activation
APVO436 Induces Target Dependent T-cell Activation CD4+ T cells CD8+ T cells 1 pM 2 pM EC50 values in activation assays APVO436 Induces T cell Activation of CD4 and CD8 T cells and Induces Proliferation of Both T-cell subsets (data not shown) CD4+:CD69% 100 80 60 40 20 0 0.01 0.1 1 10 100 1000 10000
Slide 52: APVO436 Induces Target Dependent T-cell Proliferation
APVO436 Induces Target Dependent T-cell Proliferation EC50 values in activation assays CD4+ T cells CD8+ T cells 2 pM 2 pM CD4+ T-cell Proliferation % Dividing T-cells 80 60 40 20 0 0.01 0.1 1 10 100 1000 10000 CD8+ T-cell Proliferation Molm-13 C4-2B Concentration (pM)
Slide 53: APVO436 Inhibits Tumor Growth in Xenograft Model of Human AML
APVO436 Inhibits Tumor Growth in Xenograft Model of Human AML Tumor Volume Mean Tumor Volume (mm3) 1750 1500 1250 1000 750 500 250 0 0 4 8 12 16 20 24 28 32 Days post tumor cells engraftment APVO436 Treatment Molm-13/Luc only No T cells, Vehicle control No T cells, APVO436, 3 μg Molm-13/Luc + Hu T c
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