Advantageous Technologies, Exceptional Results

Yeast Display-Based Discovery and Optimization Technologies AvantGen Company Overview

• Services and Collaborations – San Diego-based leader in providing antibody discovery and optimization services based on its state-of-the-art yeast display technology platform • Rapid discovery of human • Exceptional antibody humanization and optimization • Rabbit mAb generation for IHC and PK/PD studies • Core technologies – Superior antibody yeast display platform • Proprietary, inducible, secretable display motif – Comprehensive human antibody database – Large collection of human antibody libraries • Team – Proven expert R&D and business leaders in therapeutic antibodies

2 Yeast Display is a Superior Platform

• Widely recognized as a preferred technology platform for rapidly discovering and optimizing mAbs of exceptional quality for therapeutic development

• Can also be used to optimize and humanize antibodies originating from in vivo immunization or in vitro approaches

3 Core Platform Technology Advantages

Comparison of in vitro Antibody Discovery and Optimization Platforms Features Phage Display Yeast Display

Antibody Format Limited Extensive

Display Diversified Limited/Biased Excellent Libraries ¹

Developability Low High

¹ Yeast System Provides Improved Display of Diversity Across Diverse Human Antibody V Families vs. Phage

Phage Display Yeast Display

4 Core Platform Exceptional Human Antibody Libraries

• Constructed to mimic natural sequence variation in human antibodies to reduce immunogenicity and increase developability • Informed by deep-sequencing of human antibody repertories from > 500 individuals • Largest known collection of yeast display libraries (>100 billion clones in Fab, scFab, and scFv formats) • Most potentially problematic sequence motifs have been removed from the library  Glycosylation sites  Cleavage sites  Isomerization sites  Oxidation sites  Deamidation sites  Free cysteines 5 Rapid and Efficient Discovery of Human Antibodies for Therapeutic Development

Individual yeast clones seeded into 96-well plates. Culture SNs used for 96 well assays 10 weeks to identify 10s-100s suitable clones

6 Core Platform Antibody Optimization

Fold Sample ID K (M) K (1/Ms) K (1/s) Full R^2 D on off Improvement

WT 5.24E-07 2.75E+05 1.44E-01 0.99 1 Clone A 2.60E-10 6.08E+04 1.58E-05 0.99 2000 Clone B <1.0E-12 8.28E+04 <1.0E-07 0.99 >1000

• Focused libraries are constructed based on our proprietary database for the specific antibody clones to be optimized

• Libraries are displayed with AvantGen’s yeast display system and screened with ultra-high throughput FACS

• Affinity improvement (correlates with drug potency) of >1,000 fold can be achieved by just one round of library construction and screening

7 Core Platform Antibody Affinity Maturation Target: with 12-transmembrane regions Antigen: Soluble form not available Screening: Using cell lysate prepared from transiently transfected cells that express target-GFP fusion

WT clone

Affinity matured Clone, F10

Antibody display only Antibody display and Antibody display and Antibody display and in the presence of 10% in the presence of 10% in the presence of 10% cell lysate (target-GFP) cell lysate (target-GFP) cell lysate (target-GFP)

Plus WT soluble IgG as Plus control soluble IgG as competitor competitor 8 Yeast Display Platform Extension: Rabbit mAbs

• Coupling rabbit immunization and yeast display library screening to generate rabbit mAbs • Ultra high specificity capable of recognizing ̶ Single point mutation ̶ Post modification sites ̶ Differential cleavage sites ̶ Anti-idiotype antibodies • High affinity clones: pM to sub-nM range

9 Novel Rabbit Monoclonal Antibodies Generated with AvantGen’s Platform

Antigen Clone Affinity Peptide sequence (nM) AVG300 D4 0.01 LALQAQPVPDELVTK AVG301 E11 0.01 DITSDTSGDFR AVG308 A6 0.04 Phospho-peptide specific VADPDHDHTGFLTEyVATR

AVG309 H4 0.04 Phospho-peptide specific KD =40 pM RPHFPQFsYSASGTA AVG308: VADPDHDHTGFLTEyVATR AVG310: VADPDHDHTGFLTEYVATR y indicates phosphorylated residue

10 Isoform-Specific Rabbit Monoclonal Antibodies

HbS: VHLTPVEKSAV HbA: VHLTPEEKSAV HbC: VHLTPKEKSAV HbF: GHFTEEDKATITS

11 Rabbit Monoclonal Antibodies for IHC and PK Studies (Anti-Idiotype)

Anti-target Fab, clone E12 4

3.5

3

2.5

2

1.5

1

0.5

Isotype control Rabbit anti-target 0 clone B4 1 2 3 1. Target: Human Fab Scale bar = 50 mm 2. Irrelevant human Fab A 3. Irrelevant human Fab B

12 Typical Timelines*

Project Method/Goal Timeline Antigen-Specific 2 months Novel Fully Human Antibody Discovery Antigen- and epitope-specific 2-3 months (e.g., blocking antibody)

CDR grafting 2 months Antibody Humanization Epitope-guided selection of CDR-H3 focused library 2-3 months

Affinity Optimization Affinity improvement: 10 to 1000-fold 2-3 months

Rabbit Monoclonal Rabbit immunization, library construction and 5-6 months Antibody Generation screening /sub-nM binders

* Time to positive hits, excluding the time needed for subcloning and antibody production

13 Excellent Collaborative Record

14 Accomplished Leadership

• Xiaomin Fan, Ph.D. – Founder, President & CEO – Founded AvantGen in 2006; Inventor of the company’s technology platforms – Previously, Scientist/Sr Scientist/Group Leader, Targeted Molecules Corp. • Therapeutic antibody programs partnered with Sanofi; currently in Phase II and I trials – Ph.D., University of Kansas; Post-doc, University of Pennsylvania

• Tom Smart – Head, Corporate Development – Biopharma business leader with multiple Board and CEO appointments – Prior C-level and BD positions at therapeutic antibody technology pioneers AnaptysBio, Chairman & CEO (NASDAQ: $2B mkt cap); XOMA, CBO; Cell Genesys (Abgenix/Amgen), and other business roles at Genetics Institute (Pfizer) and Searle (Pfizer) – BS, Cornell University; MBA, University of Chicago Booth School of Business

• Catherine Woods, Ph.D. – Vice President of Research – Joined AvantGen in 2007; Broad and extensive experience (>20 years) in the pharmaceutical and biotech industry – Previously, Exec Director, Research, Targeted Molecules Corp; Assoc. Director, Clinical Research/Sr Director, Biological Research & Tech Transfer, Alliance Pharmaceutical Corp; Research Fellow, Merck Research Laboratories – Ph.D., University of California, Davis; Post-doc, California Institute of Technology

15 Case Studies

Internal projects pursed to highlight the performance advantages of AvantGen’s human antibody discovery and optimization platform

1. Anti-CD16a based NK cell engager platform

2. Anti-BCMA antibodies for multiple myeloma therapy

16 Significant Interest in NK Cell Engagers

August 27, 2018 Globe Newswire Affimed Announces Collaboration with Genentech to Develop Novel NK Cell Engager- based Immunotherapeutics for Multiple Cancer Targets

Affimed will receive $96 million upfront and committed funding and is eligible for up to an additional $5.0 billion including milestone payments, and royalties on sales

October 1, 2018, Cision PR Newswire Dragonfly Therapetics Announces New Multi-Target Collaboration with Merck to Use Dragonfly's Proprietary TriNKET™ Platform to Develop Novel Drug Candidates for Patients with Solid Tumors

Dragonfly to earn up to $695 million in up front and milestone payments per program as well as royalties on sales of approved products

17 Example From an In-house Project

• Target antigen: CD16a • Part of effort to generate NK cell engager platform – identify highly specific anti- CD16a antibody clones • Affinity to CD16a is important for the clinical efficacy of anti-cancer therapeutic antibodies • CD16a expressed on natural killer cells, macrophages, subpopulation of T-cells • A single nucleotide polymorphism creates higher Fc-binding (176V) and low Fc- binding (176F) forms. 60% populaon has 176F and 40% with 176V → bind both • CD16b expressed in 70% of leukocytes (CD16b+ granulocytes) → avoid binding

Ideal profile of the antibody candidates

CD16A(176V) CD16A(176F) CD16B Activate NK cells   X 

18 Alignment of CD16a and CD16b

CD16a and CD16b have 98% homology

Ideal antibody would exhibit high affinity and specificity against both allotypes of CD16a (176F and 176V), without cross-reactivity to CD16b The three green residues represent the only specific differences between the two CD16a allotypes and the two CD16b allotypes

19 Discovery of CD16a Specific Human Antibodies

Screening of AvantGen’s yeast display human antibody libraries

Enrichment sort MACS Enrichment sort For both 176V and 176F binders

FACS Subtractive sort Removal of CD16b binders

ELISA

CD16a-expressing-293F

FACS analysis of CD16b-expressing-293F individual clones Untransfected293F

20 The Anti-CD16a Antibody Clones are of High Affinity/Specificity Antibody DNA subcloned from yeast into mammalian expression vector; purified antibody from ExpiCHO cells used to determine KD values

21 HPLC Analysis of IgG1-A2 and IgG1-Affimed After Protein A Chromatograph Purification

Histidine in the buffer Histidine in the buffer

IgG1-A2 IgG1-Affimed

22 Affinity Comparison of Anti-CD16A Clone A2 and Affimed’s Antibody by Octet

A2/Affimed have comparable binding affinity to CD16A, with no detectable cross-reactivity to human CD16B

Human CD16A Human CD16B Cyno CD16A

IgG1-A2 1.28 nM Not detectable 6.6 nM

IgG1-Affimed 1.70 nM Not detectable 15.2 nM

23 Clone A2 in a Bispecific Format Activates CD16a Reporter Cells in a Target Cells-Dependent Manner

aCD19

aCD16A

scFv-scFv format

24 Design of Protease-Cleavable Bivalent NK Cell Engager

Protease cleavage site

(28 mg/mL from ExpiCHO under unoptimized condition)

150000 A2-Fc (No Raji) A2-Fc (+Raji) 100000

50000 Luminescence(RLU) 0 -13.5 -12.5 -11.5 -10.5 -9.5 -8.5 -7.5 -6.5 Bispecific Antibody, Log [M]

25 Clone A2 is More Thermostable Than Affimed’s Antibody

Name Format Tm1 (℃) Tm2 (℃) Tm3 (℃)

CD19-CD16a-A2 scFv-scFv 57.5 (CD19) 75.6 (CD16a) -

CD19-CD16a-Affimed scFv-scFv 62.10 (CD19 & CD16a) - - CD19-CD16a-A2-Fc scFv-scFv-Fc (IgG4) 59.2 (CD19) 65.9 (CH2) 73.1 (CD16a)

CD16A, A2 IgG1 70.9 (CH2) 89.7 (Fab)

CD16A, Affimed IgG1 70.9 (CH2) 80.4 (Fab) - CD19-CD16a, - TandAb 45 (CD19) 57.5 (CD16a) Affimed*

* Based on Affimed’s report

26 NK Cell Engagers Mediate Lysis of Raji Cells by Primary NK Cells

Raji cells are known to be resistant to NK lysis, because they express HLA-A*03 ( to inhibitory KIR3DL2) and Cw*03 and Cw*04 (group 1 and 2 of HLA-C ligands to inhibitory KIR2DL2/3 and KIR2DL1)

Cytotoxicity 50 CD19-CD16a-A2 40 CD19-CD16a-Affimed 30 20 10 0 -14 -13 -12 -11 -10 -9 -8 -7

Specific killing (%) killing Specific -10 -20 Antibody concentration [log M]

Target cells: Raji loaded with Calcein AM Effector cells: PBMCs from a healthy donor Incubation time: 3.5 hours (PBMC:Raji = 50:1)

27 2nd Example

Anti-BCMA antibody outperforms GSK’s J6M0 antibody in ADC format for multiple myeloma therapy

Target: B-cell maturation antigen (BCMA). The ECD is about 9.6 kDa

Screening of AvantGen’s yeast display human antibody libraries

45 unique anti-BCMA clones identified

3 clones effectively internalized upon binding to BCMA

Clone A11 further characterized

28 AVG-A11 Does NOT Bind hBAFFR or hTACI, Two With Homology to BCMA

2.5 2.0 BAFFR 1.5 Positive control antibody: 1.0 eBioscience, anti-hBAFFR, OD450 0.5 clone 8A7,Cat#14-9117-82 0.0 Hu-TACI Hu-BAFFR Baculovirus Cy-BCMA-Fc Hu-BCMA-Fc Hu-BCMA-His TACI Positive control antibody: eBioscience, anti-hTACI, clone 11H3,Cat#13-9217-82

FACS ELISA AVG-A11 binds to both human and cyno BCMA protein, but AVG-A11 does not bind to 293F cells transiently not to homologous proteins or baculovirus coated wells transfected with the human hBAFFR or hTACI

29 AVG-A11 Triggers More Effective BCMA Internalization Than J6M0

AVG-A11 1.85 nM GSK-J6M0

Internalization assay AVG-A11 or GSK-J6M0 were incubated with IncuCyte® FabFluor before adding to the cells. Fluorescent intensity was monitored and recorded for 38 hours.

30 AVG-A11 Out-Performs GSK-J6M0 in Killing MM Cells in an ADC Format

High BCMA level cell line: Low BCMA level cell line: H929 (3 days) MM.1S and RPMI8226 (6 days)

H929 Cells MM.1S Cells RPMI8226 Cells Antibody Fold better than Fold better than Fold better than IC50 (nM) IC50 (nM) IC50 (nM) GSK-J6M0 GSK-J6M0 GSK-J6M0 AVG-A11 0.79 0.55 0.51 4.4 3.1 5.3 GSK-J6M0 3.5 1.7 2.7

Cell viability assay Cells were incubated with the indicated concentration of primary antibodies, AVG-A11 or GSK-J6M0, in the presence of Fab anti-human-Fc-MMAF for 3 or 6 days.

31 MMAF Conjugated AVG-A11 Exhibits Highly Potent Toxicity to MM Cells, but not to BCMA Negative Cells

IC50 (nM) Direct conjugation ADC H929 U266 MM.1S RPMI8226 Raji

Phenyl650 HIC profile AVG-A11 -MMAF 0.074 0.10 0.16 0.18 >1000 of AVG-A11-mc-MAFF

Average DAR: 4.0 Cell viability assay Cells were incubated with the indicated concentration of AVG-A11- MMAF for 6 days. Total ATP amount was measured with CellTiter-Glo

32 AVG-A11 Blocks the BCMA-BAFF Interaction, and Out-Performs GSK-J6M0 in Blocking BAFF Induced NF-k Activation

100 80 60 40 Binding(%) 20 0

ELISA AVG-A11 Fab blocks BCMA binding to BAFF-coated wells ELISA Reporter Assay AVG-A11-IgG is 3.7 fold more AVG-A11 is 6.1 fold more potent than GSK- potent than GSK-J6M0 in J6M0 in inhibiting NF-k activation blocking BCMA’s binding to BAFF

33 AVG-A11 Activates CD16a (ADCC) More Effectively Than J6M0

Target cells: H929 Report cells: Jurkat-CD16a-NFAT

34 AVG-A11 Exhibits Better Developability Than GSK-J6M0

HPLC analysis Antibodies were purified using a protein A column and analyzed by HPLC (Yarra™ 3 µm SEC-3000 LC Column)

AVG-A11

GSK-J6M0

35 AVG-A11 and GSK-J6M0 Exhibit Similar Affinity and Thermostability

Affinity analysis

Antibody Fab binding to captured BCMA at 30oC (by Octet)

AVG-A11 GSK-J6M0 KD(M) Kon(1/Ms) Koff(1/s) KD(M) Kon(1/Ms) Koff(1/s)

Human BCMA 1.05E-09 5.78E+05 6.05E-04 1.33E-09 2.38E+05 3.15E-04

Cyno BCMA 4.37E-09 5.47E+05 2.39E-03 3.41E-09 2.39E+05 8.15E-04

Thermostability analysis

AVG-A11 GSK-J6M0 Tm (oC) 70.76 71.72

36 AVG-A11-MMAF Exhibited Cytotoxicity to BMMCs Isolated From MM patients, but not From a Healthy Individual

Cell viability assay

About 200 K per well of BMMCs from two patients and normal BMMCs from one healthy individual were cultured in the presence of the indicated amount of AVG-A11-MMAF for 3 days. The amount of ATP was quantified with CellTiter-Glo.

37 Summary of the Head-to-Head Comparison Data

AVG-A11 GSK-J6M0 Fold Better Antibody origin Fully human Humanized

Affinity KD=1.0 nM KD=1.3 nM 1.3 Thermostability Tm=70.76oC Tm=71.72oC Similar Cytotoxicity on cells with high IC =0.79 nM IC =3.5 nM 4.4 BCMA levels (H929) 50 50 Cytotoxicity on cells with lower IC =0.51 nM IC =2.7 nM 5.3 BCMA levels (RPMI8226) 50 50 Inhibition of BCMA-mediated IC =1.8 nM IC =11.0 nM 6.1 NF-kB activation 50 50

Activation of CD16a (ADCC) EC50=1.0 nM 3.5 EC50=0.29 nM Column retention time (peak width) 0.152 min 0.179 min (shorter time indicative of better developability)

38 Advantageous Technologies, Exceptional Results

6162 Nancy Ridge Drive, Suite 150 San Diego, California 92121, USA

www.avantgen.com

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