Run Date/Time: 23OCT19 13:28 - Program Name: ZW25-101\ESMO-Asia2019\f_Waterfall_ESMO-Asia_pdf.sas

Note: Patients 1003-205 (GEA), 1003-323 (GEA), & 1003-326 (CRC) had PD but no post-baseline tumor measurements and are excluded from plot.

Part 1 and 2: 10 mg/kg QW and 20 mg/kg Q2W Patients

Run Date/Time: 23OCT19 13:28 - Program Name: ZW25-101\ESMO-Asia2019\f_Waterfall_ESMO-Asia_pdf.sas

Note: Patients 1003-205 (GEA), 1003-323 (GEA), & 1003-326 (CRC) had PD but no post-baseline tumor measurements and are excluded from plot.

Part 1 and 2: 10 mg/kg QW and 20 mg/kg Q2W Patients

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The Bispecific Antibody Zanidatamab (ZW25) Has Unique Mechanisms of Action and Durable Anti-Tumor Activity in HER2-Expressing CancersNina Weisser1, Grant Wickman1, Libin Abraham2, Jason O’Toole1, Joy Guedia1, Gesa Volkers1 , Joe Schrag3, Charles Stevens1, Kate Choi2, Bryant Harbourne1, Chi Wing Cheng1, Peter Chan1, Duncan Browman1, Mike Gold2, Neil Josephson1, Surjit Dixit1, Gerry Rowse1

1 Zymeworks Inc., 1385 West 8th Ave, Vancouver, BC, Canada; 2 Department of Immunology and Microbiology, University of British Columbia, Vancouver, BC, Canada; 3 Human Health Therapeutics Portfolio, NRC-CNRC , Montreal, QC, Canada

HER2-directed therapies have improved clinical outcomes for many patients withHER2-positive breast and gastric cancer. Despite these successes, there remains aneed to develop improved HER2-targeted therapies for HER2-expressing tumors,particularly in the setting of recurrent or metastatic disease.

Zanidatamab is actively being evaluated in clinical trials in multiple HER2 expressingsolid tumors. Studies to date show zanidatamab is well tolerated, treatment-relatedAEs are primarily Grade 1 or 2.2,3

• Zanidatamab binds HER2 in trans and has multiple mechanisms ofaction that may collectively contribute to its anti-tumor activity

• Zanidatamab mediates unique HER2 capping and superior CDC andgrowth inhibition of HER2-overexpressing tumors compared totrastuzumab, pertuzumab, and trastuzumab + pertuzumab

• Zanidatamab is superior to trastuzumab and a combination oftrastuzumab + pertuzumab in HER2-overexpressing gastric cancerxenografts

• Zanidatamab is actively being evaluated in clinical trials in multipleHER2 overexpressing solid tumors, including in HERIZON-BTC-01, aregistration-enabling clinical trial in HER2 gene amplified biliary tractcancer (NCT04466891)

Zanidatamab Monotherapy Shows Anti-Tumor Activity in Patients with Advanced HER2-Expressing Cancers

Zanidatamab is a Promising Bispecific Antibody for the Treatment of HER2-Expressing Cancers

Zanidatamab has Superior Anti-Tumor Activity Compared to Anti-HER2 mAbs in HER2 3+ Gastric Cancer Models

This study was sponsored by Zymeworks.

Abstract: 1005

Model IHC HER2 FISH HER2

GXA-3054 3+ nd

NCI-N87 3+ Amplified

nd = not determined

Xenograft Model HER2 Expression

*

*

Figure 1. A) Zanidatamab is a humanized, bispecific, immunoglobulin (Ig) G1-like antibody(Ab) directed against the juxtamembrane extracellular domain (ECD4; scFv, blue) and thedimerization domain (ECD2; Fab, green) of HER2, the same domains targeted by trastuzumab(T; tras) and pertuzumab (P; pert) and is engineered with the Azymetric™ platform1

B) Transmission electron microscopy showing the Fc, scFv and Fab domains of zanidatamab.

Zanidatamab Elicits Superior CDC and Growth Inhibition Compared to Trastuzumab + Pertuzumab

Complement Dependent Cytotoxicity

Growth Inhibition

Figure 5. A) Zanidatamab mediates potent CDC with human complement serum in HER2-overexpressing tumor cells; trastuzumab, pertuzumab, and trastuzumab + pertuzumab (1:1)are inactive. B) Zanidatamab mediates potent tumor growth inhibition in HER2-overexpressing tumor cells and is superior to trastuzumab + pertuzumab (1:1) in NCI-N87and SK-BR-3.

A

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A. GXA 3054 Gastric PDX Model B. NCI-N87 Gastric CDX Model

A B

References 1Spreter von Kreudenstein T, et al. mAbs 2013. 5:646-6542 Meric-Bernstam F, et al. ESMO 2019, Sep. 27– Oct. 1, Barcelona Spain3 D.-Y. Oh et al. ESMO Asia 2019,Nov. 22-24, Singapore4Weisser N, et al. AACR 2017. April 1-5. Washington DC, USA.

• Total IgG serum exposure was similar for all test articles in each study (data not shown)

Disease control rate defined as percentage of patients with complete response, partial response, or stable disease per RECIST 1.1† 3 of the 57 response-evaluable patients had no post-baseline disease assessment of their target lesions and are not included in the waterfall.Response-evaluable includes all patients with measurable disease who had at least one post-baseline disease assessment (per RECIST 1.1) ordiscontinued study treatment prior to reassessment due to death from any cause or clinical progression (response imputed as Progressive disease).Colorectal cancer (CRC), gastroesophageal adenocarcinoma (GEA).

Figure 2. Zanidatamab has promising anti-tumor activity as monotherapy in patients withadvanced HER2-expressing cancers that have progressed after standard of care therapies(median of 3 prior lines of therapy), including HER2-targeted agents trastuzumab (T),pertuzumab (P), T-DM1 (K), lapatinib (L) and neratinib (N)3. Results from ZW25-101(NCT02892123), a first-in-human Phase 1 study that evaluates zanidatamab in HER2-expressingcancers. Data cutoff: Sept 18, 2019..

N=54†

Zanidatamab Mediates Internalization, Receptor Depletion, ADCC and ADCP

Figure 6. Zanidatamab treatment results in A) increased antibody internalization relative totras (24 h), intracellular antibody detected by flow cytometry, B) surface HER2 depletion (24h), surface HER2 detected with non-competing anti-HER2-ECD1-AF647 antibody followingantibody treatment by flow cytometry, C) reduction of total HER2 (24 h) in SK-BR-3,determined by western immunoblotting, and D) potent ADCC and ADCP in SK-BR-3, usingdonor PBMC and donor-derived differentiated macrophage, respectively (dashed linerepresents no treatment control).

Surface HER2 DepletionInternalizationA B

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Zanidatamab Binding Forms Unique HER2 Caps & Increased HER2 Cluster Size Compared to T + P on the Cell Surface

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Figure 3. A) Zanidatamab and tras + pert (1:1) bind with increased Ab density on HER2-overexpressing SK-BR-3 by flow cytometry. B & C) Zanidatamab binding results in unique HER2capping at 5 and 15 min (arrow) by confocal microscopy. D) dSTORM analysis shows increasedHER2 cluster size following zani binding (15 min) than T, P, and T + P. B, C, D) HER2 localizationdetected on SK-BR-3 surface with anti-HER2-ECD1-AF647 Ab. See Abstract #1032 for details.

D

Figure 7. A) All test articles administered at30 mg/kg twice weekly for 5 weeks; B) Testarticles administered at indicatedequimolar dose levels twice weekly forfour weeks. *, p<0.05 vs. trastuzumab &tras + pert by linear mixed-effects model fitto log-transformed tumor volumes overtime. Differences in tumor growth ratebetween treatment groups was assessedusing a Wald test.

Phase 1 data support pivotal trial now enrolling in HER2 gene amplified biliary tractcancer (HERIZON-BTC-01; NCT04466891).We have shown that zanidatamab’s unique design and bispecific binding results inmultiple mechanisms of action including increased antibody binding density, potenteffector function, improved receptor internalization and HER2 downregulationrelative to trastuzumab4.We present recent data that further explores zanidatamab’s mechanisticdifferentiation compared to T, P and T + P.

Zanidatamab Binds HER2 in trans and Forms Large Antibody:HER2 Complexes in Solution

cis/trans Binding by SPRA B

zanidatamab* analogue, (with non-affinity matured anti-ECD2) with equivalent apparent Kd compared totrastuzumab at low antibody capture, used to control for affinity/apparent affinity differences betweenzanidatamab and trastuzumab. Surface plasmon resonance (SPR), Response Units (RU), Molecular Weight(MW), Analytical Ultracentrifugation (AUC).

Figure 4. A) Reduction in kd andapparent KD observed withincreasing zanidatamab*surface concentrations (lower)shows ability to bind HER2 intrans. B) Monospecific anti-HER2 (upper) and transzanidatamab (lower) HER2binding. C) Increased Ab:HER2complex sizes (followingequimolar Ab:HER2 mixtures)observed with zani, comparedto tras or pert, shows ability tobind HER2 in trans.

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Disease response per investigator assessment (using RECIST 1.1)

Biliary(N = 9)

CRC(N = 13)

GEA(N = 23)

All others(N = 12)

Total(N = 57)

Partial response (n [%]) 6 (66.7) 6 (46.2) 9 (39.1) 4 (33.3) 25 (43.9)

Stable disease 1 (11.1) 5 (38.5) 4 (17.4) 5 (41.7) 15 (26.3)

Progressive disease 2 (22.2) 2 (15.4) 10 (43.5) 3 (25.0) 17 (29.8)

Disease control rate 7 (77.8) 11 (84.6) 13 (56.5) 9 (75.0) 40 (70.2)

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AACR Annual Meeting 2021