Aptevo Therapeutics. ADAPTIR TM Platform: Rapid Development of Novel Protein Therapeutics. World Bispecific Summit Boston, MA September 28, 2017

Transcription

1 Aptevo Therapeutics ADAPTIR TM Platform: Rapid Development of Novel Protein Therapeutics World Bispecific Summit Boston, MA September 28, 2017 Peter Pavlik Principal Scientist

2 Agenda Overview of ADAPTIR Bispecific Technology Candidate Generation Process for ADAPTIR Platform Portfolio of Clinical Candidates Portfolio of Preclinical Candidates ADAPTIR Platform: Key CMC Advantages Summary 2

3 Overview of ADAPTIR Bispecific Technology 3

4 Overview of ADAPTIR Platform Monospecific and bispecific platform technology for novel therapeutics Robust, flexible bispecific platform enables different mechanisms of action T-cell engagers (anti-tumor x anti-cd3) Targeted cytokine delivery Targeted activation of immune cells Neutralization of soluble factors Receptor blockade +/- Fc-mediated effector function Distinct advantages over other bispecific technologies Homodimeric and bivalent binding to two targets Leverages avidity to increase potency Flexibility of platform: multiple binding domains, ligands or extracellular domains (ECD) can be attached scfv1 Fc modified to modulate effector functions scfv2 Cytokine ECD 4

5 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 T-cell CD3 engagers T-cell co-stimulators Targeted cytokines Trans signaling Trans signaling Cis signaling Induces polyclonal T-cell response Boosts endogenous T-cell response Boosts endogenous adaptive/innate response 5

6 Unique Features of ADAPTIR Bispecific Platform Technology Novel homodimer structure simplifies candidate generation Rapidly mix and match target binding domains Numerous candidates can be evaluated simultaneously IgG Fc extends half-life, up to ~12.5 days observed in rodents Antibody-like production processes Modified Fc to tailor Fc gamma receptor binding Retains binding to FcRn to achieve Ab-like half-life Single gene, ease of CHO cell line production Better yield and cost-of-goods than heterodimers Predictable manufacturability Bivalent for both binding domains, leverages avidity scfv domains are selected and optimized for affinity, specificity, and stability scfv1 Fc modified to modulate effector functions scfv2 Cytokine ECD 6

7 Next Generation ADAPTIR Scaffold Utilized for New T-Cell Engager Candidates Next generation ADAPTIR platform has been optimized for new candidates High-throughput candidate generation Stability, activity and manufacturability screens to identify best candidates Improved half-life Reduced risk of immunogenicity Improved linkers to reduce clipping scfv1 Fc modified to modulate effector functions scfv2 Cytokine ECD 7

8 IF N -g C o u n ts / D o n o r Next Generation ADAPTIR T-Cell Engager 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 ADAPTIR candidates; comparable to negative control High Response Potential risk to ADA Low Response Low risk to ADA A B C Next Generation ADAPTIR Candidates 8

9 ADAPTIR A Modular Technology Human Fv from hybridoma Human scfv Phage library Engineered proteins Monospecific Bispecific Targeted Cytokine Delivery Targeted ECD Delivery 9

10 ADAPTIR Monospecific / Bispecific Portfolio Product Candidate Technology Indication Target Pre- Clinical Clinical Development Stage Milestones/Highlights Phase I Phase II Phase III Otlertuzumab ADAPTIR Monospecif ic CLL CD37 Executing Phase 1b combination study APVO414 ADAPTIR Bispecific RTCC mcrpc Immunooncology CD3/PSMA Executing Phase 1 clinical trial APVO436 ADAPTIR Bispecific RTCC AML CD3/CD123 Preclinical in vitro and in vivo POC, lead candidate ALG.APV ADAPTIR Bispecific T-cell Co- Stimulation Multiple Solid Tumors 41BB/Tumor Antigen Initiation of CMC and IND-Enabling Activities ROR1 x CD3 ADAPTIR Bispecific RTCC Hematologic and Solid Tumors Tyrosine Kinase ROR1 Preclinical in vitro and in vivo POC, developing lead candidate Multiple ADAPTIR Candidates ADAPTIR Bispecific RTCC / New MOA Hematologic and Solid Tumors Undisclosed Multiple RTCC candidates with novel MOA APVOE210 ADAPTIR Targeted cytokine IBD IL10/CD86 Preclinical POC in IBD, CHO production cell line RTCC Redirected T-Cell Cytotoxicity = T-Cell Engager + Partnered with Alligator Bioscience 10

11 ADAPTIR Platform Candidate Generation Process 11

12 Screening and Optimization of ADAPTIR Candidates 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 stabilizing disulfides Example of 8 ADAPTIR candidates selected against a single antigen shows multiple scfvs with desired thermostability criteria: Molecule scfv1 Tm, C ADAPTIR M 70 ADAPTIR N 79 ADAPTIR O 64 ADAPTIR P 65 Molecule scfv1 Tm, C ADAPTIR R 73 ADAPTIR S 70 ADAPTIR T 69 ADAPTIR U 74 12

13 ADAPTIR Candidates are Screened to Meet Detailed Product Profile Criteria Activity and affinity consistent with desired mechanism of action Stable under manufacturing, storage and dosing conditions Function Stability In-vivo Suitability Stable in serum, no off-target binding, low immunogenicity potential 13

14 Candidates are screened for functional, conformational and colloidal stability Category Thermostability Solubility Process compatibility Storage stability Sequence liabilities Specificity, biological stability Assays DSC (Tm) DSF (Tm, T agg ) High-salt solubility screen Protein concentration screen Process intermediate stability Shear stress assessment Stability at multiple ph, temp, [protein] and platform formulation conditions PTM prediction and evaluation by MS Spatial Aggregation Propensity (SAP) Analyses Target binding affinity Non-specific binding screens (serum and cell surface) Serum stability (binding and function) Protease susceptibility 14

15 ADAPTIR Candidates are Screened for Cleavage Susceptibility DAD1 A, Sig=280,4 Ref=360,100 ( CX\ at CX Domain \ CX2 T0.D) Junctions mau DAD1 A, Sig=280,4 Ref=360,100 ( CX\ CX \ CX2 D1.D) DAD1 A, Sig=280,4 Ref=360,100 ( CX\ CX \ CX2 D2.D) DAD1 A, Sig=280,4 Ref=360,100 ( CX\ CX \141111CX2 D3.D) T0 D2 D1 D3 T0 D1 D2 D3 D6* min Construct A Construct B New candidates are selected to be resistant to proteolytic cleavage to minimize degradation products during expression and in vivo use Eliminates need for specific purification step to eliminate LMW contaminants 15

16 ADAPTIR Bispecifics Utilize Modified Fc to Eliminate ADCC and CDC Function Thermostability and FcRn binding similar to wt IgG1 Fc Molecule CH2 Tm ( o C) CH3 Tm ( o C) Functions Thermal Stability IgG1 Fc WT ADAPTIR IgG1 Fc ADCC/CDC capable ADCC/CDC null Molecule IgG subtype Molecule Type KD by SPR (nm) FcRn Affinity scfv-fc-scfv ADAPTIR IgG1 Fc (ADCC and CDC null) ADAPTIR bispecific 26 trastuzumab IgG1 WT MAb 64 etanercept IgG1 WT ECD fusion

17 ADAPTIR Molecules Achieve both Functional and Stability Objectives ID Candidate A (Lead) %Protein Loss, Salt Spike Target Binding KD (nm) scfv Tm (DSC) In vitro Activity EC-50 (pm) Candidate B Candidate C Standardized process for identifying stable, active constructs Research, process, analytical and formulation development teams review data and select clinical lead construct 17

18 ADAPTIR Molecules Are Stable Under Accelerated Stability Conditions (40 C) T=0: 0.21% HMW T=7days at 40 o C; 1.9% HMW Careful selection of lead facilitates subsequent development and cgmp manufacturing Enables rapid progression of candidates to clinic 18

19 ADAPTIR Portfolio of Clinical Candidates 19

20 Clinical Candidate otlertuzumab (CLL) acd37 scfv Human IgG 1 Fc Description 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 /NHP) vs antibody fragments Partnering 100% owned by Aptevo Actively pursuing potential partnership opportunities Development Status 253 subjects treated to date; appears safe and well tolerated Ongoing: Phase 2 study for chronic lymphocytic leukemia (CLL) Combination with ibrutinib Preliminary data read-out anticipated in H Multiple clinical trial data published, establishing clinical proof-of-concept PHASE 2 STUDY (16201): Combination of otlertuzumab + bendamustine PHASE 1b STUDY (16009): Combination of otlertuzumab + rituximab 20

21 Clinical Candidate APVO414 (mcrpc) Description 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 antibody fragments Anti-PSMA Anti-CD3 Development Status Open-label Phase 1 continuous infusion study underway (U.S. & Australia) Safety, tolerability, and clinical activity endpoints Patients with metastatic castration-resistant prostate cancer (mcrpc) Stage 1: Primary Objective MTD; Secondary Objectives: tolerability, PK, PD, immunogenicity, cytokine response, and clinical activity Stage 2: Primary Objective Evaluate clinical activity in patients that have or have not received prior chemotherapy Preliminary data read-out anticipated mid

22 ADAPTIR Preclinical Candidates 22

23 Unique Features of ADAPTIR Bispecific T-Cell Engagers Novel, proprietary humanized binding domain targeting CD3, cross-reactive with NHP Bivalent binding to target increases RTCC potency compared to monovalent bispecifics T-cell stimulation results in reduced cytokine release upon T-cell activation* Anti-tumor scfv No ADCC/CDC scfv optimized and selected in bispecific format to ensure good manufacturability and half-life State-of the art tools used to identify and remove potential immunogenic sequences Bispecific ADAPTIR Therapeutic Anti-CD3 scfv * 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 DOI: / MCT

24 APVO436: CD123 x CD3 Bispecific Preclinical Candidate Anti-CD123 scfv 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 properties Binding, activation of T cells, RTCC activity Antibody-like half-life in Balb/c mice of >12 days Preclinical in vivo proof of concept established in xenograft tumor models High titer CHO cell clone production levels Good manufacturability attributes Anti-CD3 scfv Modified Fc No ADCC/CDC 24

25 B io lu m in e s c e n c e T o ta l F lu x [p /s ] APVO436 Inhibits Tumor Growth in Xenograft Model of Human AML G r o w th o f M O L M -1 3 /L U C C e lls (B io lu m in e s c e n c e Im a g in g ) Day 11: Vehicle Control Group (Tumor + T cells) M o lm T -c e lls /V e h ic le C o n tro l M o lm -1 3 o n ly /V e h ic le C o n tro l M o lm T -c e lls /A P V O 4 3 6, 1 5 g M o lm T -c e lls /A P V O 4 3 6, 3 g M o lm T -c e lls /A P V O 4 3 6, 0.6 g M o lm -1 3 o n ly /A P V O 4 3 6, 3 g Day 11: APVO436, 0.6 g Group (Tumor + T cells) D a y s p o s t tu m o r c e lls e n g r a ftm e n t A P V O /A P V O T re a tm e n t 25

26 aror1 x acd3 ADAPTIR Candidate: Overview ROR1 Tumor Antigen Novel therapeutic that redirects T cells to kill ROR1- expressing tumor cells ROR1 expressed in a number of solid tumor indications Active in in vitro and in vivo studies at very low concentrations Competitive with other bispecific antibody formats Prolonged serum half-life in rodents NHP cross-reactive Targeting clinical development in multiple oncology indications aror1 scfv Modified Fc No ADCC or CDC acd3 scfv 26

27 M e a n T u m o r v o lu m e (m m 3 ) T im e to T u m o r p ro g re s s io n (D a y T V > m m 3 ) aror1 x acd3 Delays Tumor Growth and Improves Survival in a Xenograft Model T u m o r V o lu m e s T im e t o T u m o r P r o g r e s s io n * T r e a t m e n t s d a y s 0,4,8 D a y p o s t tu m o r c h a lle n g e * P = A D A P T 3 g x 3 v s A D A P T 1 g x 3 D a y p o s t tu m o r c h a lle n g e M D A -M B o n ly P B S / v e h ic le c o n tro l A D A P T IR 3 g (x 3 ) A D A P T IR 1 g (x 3 ) A D A P T IR 0.3 g (x 3 ) 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 27

28 APVO210: Targeted-Cytokine Delivery ADAPTIR Therapeutic for AIID Targeted-cytokine based on the bispecific ADAPTIR platform acd86 scfv Anti-CD86 scfv delivers IL-10 specifically to Antigen Presenting (CD86+) cells to suppress inflammation Inhibits antigen presentation and subsequent T-cell activation Inhibits release of pro-inflammatory cytokines No ADCC/CDC Modified form of IL-10 eliminates lymphocyte stimulation monomeric IL-10 Fc mutations eliminate effector function but retain FcRn binding CHO expression of 1.4 g/l APC 28

29 ADAPTIR Platform Key CMC Advantages 29

30 Proven PD and Manufacturing Platform EXPERIENCE 8 GMP lots across multiple molecules History of successful transfer to CMOs UPSTREAM Standard CHO cell line Titers > 1 g/l achieved for early-phase processes Successfully scaled to 2,000 L Commercially-available defined media Fed-batch processes with standard production bioreactor residence times ANALYTICAL Standard mab assays for: Characterization GMP release Stability testing FORMULATION DOWNSTREAM Three chromatography steps, mab-like capture mab-like viral inactivation and viral filtration Purification yields comparable to mabs Standard excipients Frozen DP for early phase clinical Currently use lyophilized DP for late phase clinical (>2yr stability) 30

31 ADAPTIR Expression Levels Meet Clinical and Commercial Requirements ADAPTIR Candidate Examples ADAPTIR Structure Titer (g/l) scfv-fc Mono specific ~ 2.0 scfv-fccytokine Cytokine Delivery ~ 1.4 scfv-fc-scfv Bispecific ~ 1.5 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 & commercial demands 31

32 Rapid PD from Lead to Clinic in 18 Months Aptevo employs a process & analytical development platform enabling rapid transfer from research to clinical development Lead Transfection Clone Candidates Clone Selected Upstream & Downstream Process Defined CMC Fully Defined Clinical Manufacturing Initiated IND Clone Generation Clone Selection Process Confirmation Analytical & Formulation Confirmation Process & Analytical Tech Transfer Clinical Manufacturing 18 months 32

33 ADAPTIR Summary 33

34 ADAPTIR Bispecific Technology ADAPTIR is Aptevo s monospecific and bispecific antibody platform technology for generating novel immuno-oncology therapeutics Robust, flexible platform that can be used to generate bispecific molecules with different mechanisms of action The ADAPTIR platform has distinct advantages over other bispecific technologies and therapeutic approaches Excellent stability, half-life and manufacturing characteristics Antibody-like half-life allows for improved dosing protocols Ability to reproducibly generate potent molecules that modulate the immune response to tumors 34

35 Acknowledgements Aptevo Therapeutics Aptevo Located in Seattle Research and Non-Clinical Development Molecular Biology and Protein Engineering Pharmacology and Cell Sciences Protein Sciences Immuno-biology Process Development Formulation, Analytical & Bioassay Development Mt Rainer National Park Clinical Research 35