Antibody Discovery and Bispecific Design: Development Considerations. Aaron K. Sato, Ph.D. LakePharma, CSO
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1 Antibody Discovery and Bispecific Design: Development Considerations Aaron K. Sato, Ph.D. LakePharma, CSO
2 My First Chemistry Set
3 The Chemistry Set In 1914, American chemist John J. Porter produced the first line of chemistry sets, Chemcraft.
4 Overview LakePharma and the Antibody Center Antibody Discovery Developability Bispecific Design and Testing Brief Overview of Expression Systems
5 LakePharma Biologics company focusing on providing integrated solutions Founded in 2009 and based in San Francisco Bay Area Named as an Inc Fastest Growing Companies in 2015 and 2016 Named on San Francisco Business Times list of 100 Fastest Growing Private Companies in the Bay Area in 2016 Acquired Blue Sky BioServices (Worcester, MA) in March 2016 ~150 employees, 30% have PhDs LakePharma is the largest US-based biologics CRO, with most complete capabilities Company mission is to provide industry-leading protein engineering and biomanufacturing services
6 Who is LakePharma? LakePharma is a biotech company that enables and supports the discovery and development of the biologics of tomorrow Discovery Engineering Development Manufacturing
7 LakePharma s Integrated Solutions for Drug Development and Manufacturing Our technical capabilities cover the entire spectrum of biologics development and analytics We can take drug program from idea to lead to stable cell line to a formulated protein
8 LakePharma Antibody Center Focus on antibody No downstream development Cell Biology Antibody Discovery Antibody Engineering Protein & Analytical Science BioExpression Stable Cell Line Development Cell-based Binding Assays Functional Assays (in vivo focus) Hybridoma Campaign Assay Development to Support Hybridoma Tech Transfer (in vitro focus) Phage Display Ribosome Display DNA Cloning HT Screening HT Ab fragment expression/purific ation (E. coli) Affinity Maturation Assay & Analytics Bispecific Antibody Developability Assays Humanization Immunogenicity Assessment (in silico) High Throughput Expression Hybridoma Sequencing Recombinant Antibody Production DNA cloning DNA scale Up Single B-cell Technologies
9 Multiple shots on goal for antibody discovery and engineering
10 Antibody Structure
11 Fundamental Breakthroughs in Therapeutic Antibodies Human and humanized antibodies Abgenix, Medarex, PDL and others Specialized Antibodies FDA-approved therapeutic antibodies Human or humanized mabs $37.9B (2012 U.S. sales) Murine or chimeric mabs New state-ofthe-art for ADCs: homogeneity, site-specific conjugation ProteinSAR bispecifics: optimal structures for superior drug-like properties
12 Source of Antigen Tagged Antigen Fc Fusions His Tag BirA Tag Enzymatic Biotinylation Cell-based Antigen Stable CHO line over-expressing antigen Tumor cell line that expresses antigen Primary cells/tissues expressing antigen
13 Source of Antibodies and Integration B-Cell Based Technologies Phage Display Cell- Based Display Ribosome Display Bispecifics Many Scaffolds Antibody Engineering Engineered Antibody nnaa Linkerwarhead ADCs
14 Phage Display >10 9 different antibodies
15 Library Types Naïve Immune Synthetic Ag Specific Immune Lower affinity to human antigen? Requires careful design Higher affinity and broader epitope space? Focused effort Developability?
16 Phage Display Selection
17 Ribosome Display How & what? Antibody Antigen-biotin Streptavidin capture Limited to recombinant protein selections mrna Ribosome PCR amplify Screen output IVTT + Ag No Ag CDR H3 Round 1 Round 2 Affinity Maturation Round 3 Round 4 Naïve Libraries (Synthetic)
18 KD (nm) Ribosome Display A Tool for Lead Optimization Rd1 +Ag -Ag Rd2 Rd Parent New lead Recovered protein (ug/ml) Improved clones Parent KD vs protein recovered Cell Binding ELISA
19 Mouse Hybridoma (Köhler/Milstein, 1975) Nobel Prize, 1984
20 Hybridoma High affinity antibodies specific to Ag Cross-reactivity to host Ag difficult! Source of diversity Mouse, Rat, Rabbit, Chicken, Humanized equivalents Multiple immunization approaches Recombinant protein Cells DNA Requires humanization Good precedence for developability The in vivo filter
21 The Process of Humanization
22 Example: An Approach to Humanization MuHC HC-1 HC-2 HC-3 HC-4 MuLC LC LC LC LC DNA Synthesis 4 HC and 4 LC grafts with murine HC/LC controls Express Antibodies 5x5 matrix = 25 IgGs Test for: (vs. muparent) Assembly/Titer Affinity: SPR Thermal Stability FACS Binding Functional Activity
23 Immortalized Human B-cell Technologies After immortalized through various methods, screening workflow similar to hybridoma Limited exposure to this technology Pro: Human Antibody Con: Immunization?
24 Cell-based Display Technologies Eukaryotic Processing Machinery Like the in vivo filter? Bacterial Yeast Mammalian Advantages over phage display? FACS driven selections Affinity maturation More difficult, but worth it
25 PP9650_DG_R_ _SEC 399 (3.577) M1 [Ev ,It19] (Gs,0.800,1034:3697,0.20,L33,R33); Sb (15,2.00 ); Cm (395:399) % : TOF MS ES+ 9.13e6 mass PP9650_DG_R_ _SEC 345 (3.114) M1 [Ev ,It27] (Gs,0.800,1132:2662,0.50,L33,R33); Sb (15,2.00 ); Cm (342:347) % : TOF MS ES+ 6.15e6 mass Developability Assessment In silico DNA Sequence check and Protein Sequence Hot Spot Analysis, followed by Mass Spec verification DNA codon preference Protein sequence hot spot analysis Productivity Readiness Check Transient production in HEK293 or CHO system Intact Mass CE-SDS Light Chain Heavy Chain Integrity and Stability Check (to demonstrate whether the antibody is stable biochemically) Intact Mass/Peptide Mapping/ PTM by Mass Spec DSF/DLS Thermostability assessment Aggregation/Fragmentation/PTM and Glycan profiling over 2 weeks incubation under stressed conditions SE-HPLC/LabChip CE-SDS DSF/SLS HPLC O D B s A b P o ly -S p e c ific ity E L IS A R e f 1 R e f 2 R e f 3 R e f 4 P C DLS u g /m L 5 0 u g /m L 1 7 u g /m L 2 n d A b o n ly PK Readiness Check Poly-specificity ELISA, Surface hydrophobicity assay Specificity requirement
26 Case Study: mab PPXXXX Ready to Move Forward Purity requirement rce>95% Purity requirement nrce>90% Sample ID %LMWC %(HC+LC) %MMWC %HMWC mab reduced N/A N/A mab non-reduced N/A N/A
27 Case Study: mab PPXXXX Ready to Move Forward SE-HPLC (Mab-Pac1) Monomeric state 3 mau min Peak # Peak Size (kda) Peak Area % Peak ID 1 ~ Aggregate 2 ~ Aggregate 3 ~ Monomer Notes
28 Case Study: mab PPXXXX Ready to Move Forward Intact mass measurement Integrity of the molecule Intens. x WangS_i5615_PP6410red_Ldp800_34_01_15896.d: +MS, min, Smoothed (0.19,1,GA), Baseline subtracted(0.00), Deconvoluted (MaxEnt) Intens. WangS_i5615_PP6410red_Ldp800_34_01_15896.d: +MS, min, Smoothed (0.19,1,GA), Baseline subtracted(0.00), Deconvoluted (MaxEnt) x Light Chain m/z Intens. x WangS_i5615_PP6410red_Ldp800_34_01_15896.d: +MS, min Heavy Chain m/z m/z Heavy Chain Light Chain Measured Mass Da Da Predicted Mass Da Da Delta Mass Da 0.13 Da
29 Case Study: mab PPXXXX Ready to Move Forward cief Charge variants profiling Peak # pi Peak Area % Peak ID Notes Acidic Peak Group Main Peak Basic Peak Group
30 Case Study: mab PPXXXX Ready to Move Forward DSC Thermostability DSF Thermostability and Aggregation onset ANALYSIS Peak # Tm ( C) ΔH cal (kj/mol) Tagg266: 70.7 C
31 Case Study: mab PPXXXX Ready to Move Forward Affinity measurement against Antigen in BLI or SPR Affinity requirement Method Loading Sample ID Sample ID KD (M) kon(1/ms) kdis(1/s) Full X^2 Full R^2 Octet Antigen PPXXXX 1.30E E E
32 Case Study: mab PPXXXX Ready to Move Forward Poly-specificity ELISA, Surface hydrophobicity assay Specificity requirement 5x uncoated background 5x uncoated background HEK293 WCL and BVP ELISA showed consistent results, which serve as good PK indicators. Analysis Peak # Peak Peak Size Area % (kda) Peak ID 1 ~ Aggregate 2 ~ Monomer 3
33 Countless Bispecifics Scaffolds are Continually Being Developed Biology may dictate the best format to use Is there a one size fits all format? Ideally, it would be good to have a variety of formats available Speiss et al 2015 review
34 An Example of Specialization Bispecific T-cell Engager
35 Many Different Bispecifics are in Clinical Trials Kontermann et al 2015 review
36 X Bispecifics by Activity Dual Targeting Bi- Epitopics/Paratopics Act directly on multiple target structures Dual binding to non-overlapping target epitopes Coupled with Delivery of X Coupled with Delivery of X X
37 Focus on Dual Targeting Same Cell Dual Targeting Soluble Ligand & Cell Target Bispecific T-cell Engagers (BiTEs) Different Cells Bispecific NK-cell Engagers All others that do not recruit immune cells
38 My Bispecific Risk Scorecard Evaluation Criteria Case Study: Criteria Cost of Goods (0-3, Low to High) Ease of use (0-3, Easy to Hard) Time to discovery (0-3, Short to Long) Does it look like an antibody? (0, Yes; 2, No) Potential for immunogenicity (0-3, Low to High) Biophysical properties/stability (0-3, Stable to Unstable) Advantage over cocktail of antibodies (0, Yes; 1, No) Half-life extension (0, Yes; 3, No) Total Grade Lower is better!
39 My Bispecific Risk Scorecard Evaluation Criteria Case Study: IgG-scFv: EGFR x IGFR, IGFR (Dual Epitopes) Morrison-type Bispecific Criteria Cost of Goods (0-3, Low to High) 1 Ease of use (0-3, Easy to Hard) 1 Time to discovery (0-3, Short to Long) 1 Does it look like an antibody? (0, Yes; 2, No) 2 Potential for immunogenicity (0-3, Low to High) 2 Biophysical properties/stability (0-3, Stable to Unstable) 0 Advantage over cocktail of antibodies (0, Yes; 1, No) 0 Half-life extension (0, Yes; 3, No) 0 Total 7 Grade
40 My Bispecific Risk Scorecard Evaluation Criteria Case Study: FIT-Ig Criteria Grade Cost of Goods (0-3, Low to High) 1 Ease of use (0-3, Easy to Hard) 1 Time to discovery (0-3, Short to Long) 1 Does it look like an antibody? (0, Yes; 2, No) 2 Potential for immunogenicity (0-3, Low to High) 2 Biophysical properties/stability (0-3, Stable to Unstable) 0 Advantage over cocktail of antibodies (0, Yes; 1, No) 0 Half-life extension (0, Yes; 3, No) 0 Total 7
41 Case 1: FIT-Ig (Fabs-In-Tandem Ig) Tetravalent bispecific molecule Symmetric Correct pairing of VH/VL Flexibility allowing dual binding CH2 CH3 CH2 CH3 Linker is optional Heavy chain N - VL A CL VH B CH1 CH2 CH3 -C Light chain N - VL B CL -C Short chain N - VH A CH1 -C
42 Case 1: FIT-Ig Expresses Well Like IgG ProA purification Transient yield >300 mg/l Heavy chain Light chain Short chain VL A VH A N - N - CL VH B N - VL B CH1 -C CH1 CL CH2 -C CH3 -C FITIG (from HEK293) (NR) FITIG (from HEK293) (R) A generic IgG (NR) A generic IgG (R)
43 Case 1: SE-HPLC Profile Showed High Monomeric Content Molecular weight standar FIT-Ig
44 Case 1: Antigen Binding Arms Function Independently Binding of antigen 2 remains the same whether antigen 1 is present or not Flow Antigen 1 Flow Buffer Flow Antigen 2 Flow BsAb Loading Sample ID Sample ID KD (M) kon(1/ms) kdis(1/s) Full X^2 Full R^2 Antigen 2 on rate: With Antigen 1: 2.4 E5 Without Antigen 1: 2.5 E5 FIT-Ig Antigen 1 8.7E E E FIT-Ig Antigen 2 5.2E E E FIT-Ig Retains Full Functions of Parental IgGs Neutralization Potency IC50 (pm) mab1 mab2 FIT-Ig Antigen Antigen
45 Case 1: FIT-Ig Has Similar Thermostability as IgG FIT-Ig IgG
46 Case 1: FIT-Ig Displays IgG-like PK Profile Serum concentration (ug/ml) Serum concentration (ug/ml) FIT1-Ig IV Time (day) FIT1-Ig SC 0 7 Time 14 (day) Parameter Unit Antigen 1 Capture ELISA method Antigen 2 Capture Cl ml/day/kg Vss ml/kg t 1/2 day AUC last day*ug/ml AUC INF day*ug/ml MRTI NF day PK parameters Unit Antigen 1 Capture ELISA method Antigen 2 Capture Tmax day Cmax ug/ml Terminal t 1/2 day AUC last day*ug/ml AUC INF day*ug/ml CL/F ml/day/kg F %
47 Expression Systems
48 Contact Information Aaron K. Sato, Ph.D. LakePharma CSO P: Ext. 250 F: Harbor Blvd, Belmont, CA
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