ZW49, A HER2-Targeted Biparatopic Antibody Drug Conjugate for the Treatment of HER2-Expressing CancersKevin J. Hamblett, Stuart D. Barnscher, Rupert H. Davies, Phil W. Hammond, Andrea Hernandez, Grant R. Wickman, Vincent K.C. Fung, Tong Ding, Graham Garnett, Adam S. Galey, Patricia Zwierzchowski, Brandon C. Clavette, Geoffrey C. Winters, Jamie R. Rich, Gerry J. Rowse, John S. Babcook, and Diana HausmanZymeworks Inc., Vancouver, BC, Canada and Zymeworks Biopharmaceuticals, Seattle, WA

Contact information: info@zymeworks.com

P6-17-13

AcknowledgementsWe would like to thank Ryan Dercho, Tiffany Tolm ie, David Poon and Tony Polverino for their review of the poster.

ZW49 – Anti-HER2 Biparatopic Antibody-Drug ConjugateBiparatopic antibody (ZW25) targets two distinct HER2 epitopes• Same domains as trastuzumab (ECD4) and

pertuzumab (ECD2)ZymeLink Auristatin ADC enhanced therapeutic index•Proprietary linker-drug conjugated via disulfides containing a cleavable linker and novel auristatin payload

ZW49 Internalizes and Traffics to Lysosomes in HER2 Expressing Cells to Greater Levels and More Rapidly Than Monospecific ADC

ZW 49 + αHuFc-pHAb

2 Hr 4 Hr 6 Hr 24 Hr

Trastuzumab-ZymeLinkAuristatin + αHuFc-pHAb

• BT-474 HER2 positive ductal breast carcinoma• Animals intracranially implanted on

Day 0• IV dosing commenced on Day 8• IV dosing once weekly (qw) for T-DM1,

Control conjugate, and Vehicle or once every two weeks for 6 weeks (q2wx6) for ZW49 and T-Exatecan Derivative • N=7/cohort• Body weight measured twice a week

until D18 and daily thereafter

To determine internalization, pHAb, a highly fluorescent dye at acidic pH (pink), was coupled to amines of a αHuFc. αHuFc-pHAb and ADCs were incubated with HER2-expressing cell lines and fluorescence measured using a high content CellInsight™.

Summary• ZW49’s biparatopic antibody enhances internalization and lysosomal trafficking compared to a monospecific HER2-targeting ADC• Complete tumor regressions observed in Low to High HER2-expressing models• ZW49 efficacy observed in HER2-high breast cancer brain metastasis model• ZW49 was well tolerated in non-human primates (Q2W dosing for 4 doses) with an HNSTD of 18 mg/kg• Toxicology results support clinical dosing well above predicted efficacy levels• Expanded therapeutic window of ZW49 may enable higher doses and greater exposures leading to improved anti-tumor activity in patients with

High and Low HER2-expressing cancers• Investigational New Drug (IND) application filed in 2018, Phase 1 clinical trial planned to initiate in early 2019

ZW49 is active and well-tolerated in preclinical studies •Active in HER2-low to HER2-high patient derived xenograft (PDX) models•Well tolerated at 18 mg/kg in repeat dose toxicology studies in non-human primates

SK-BR-3

DNA/Nuclei: cyan Lysosomes: yellow pHAb dye: pink/white

BackgroundFollowing T-DM1, multiple novel HER2-targeted antibody drug conjugates (ADCs) have been developed with the promise of improved potency and efficacy. The preclinical characterization of a new anti-HER2 biparatopic ADC, ZW49, combines the potential for improved potency and greater tolerability due to the unique properties of Zymeworks’ Azymetric™ and ZymeLink™ platforms. ZW49 was generated from the conjugation of our proprietary ZymeLink Auristatin to the Azymetric anti-HER2 IgG1, ZW25, via a protease cleavable linker. The Azymetric biparatopic antibody of ZW49 demonstrates lysosomal trafficking and superior internalization relative to a HER2-targeted monospecific ADC. The unique properties of the ZymeLink Auristatin of ZW49 enable greater tolerability and exposure. These properties enable ZW49 to generate complete responses in HER2 low to high-expressing PDX models at exposures tolerated in non-human primates.

HER2

ECD4

HER2ECD2

ZW49

Test ArticleDose

(m g/kg) Schedule

M edian Survival

(days)

M edian Survival p-value com pared

to T-DM 1

M edian Survival p-value com pared to

T-Exatecan Derivative

ZW 49 6 q2wx6 98 0.00323 0.0224

T-ExatecanDerivative

6 q2wx6 66 0.396 N/A

T-DM 1 6 qw 60 N/A 0.396

Predicted Therapeutic Window of ZW49 Allows Doses Resulting in Regressions of HER2 Low Tumors

ZW49 Exhibits Efficacy in Panel of HER2-Mid and HER2-High Breast Cancer Xenograft Models Compared to T-Exatecan Derivative and T-DM1Toxicology Results Support Clinical Dosing of ZW49 Above Predicted Efficacious Doses

ZW49 Exhibits Similar Pharmacokinetics to Naked Antibody ZW25 in Non-Human Primates

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GLP Toxicology Study0, 6, 12, 18 mg/kg

4 doses at 2 week intervals6 week recovery

Highest Non-Severely Toxic Dose (HNSTD) 18 mg/kg

• ZW49 is well tolerated in non-human primates• No clinical observations were considered adverse

• No mortality on study• No significant change in body weight• No clinical pathology findings were considered adverse

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ZW49, 12 mg/kg (ST910)ZW49, 6 mg/kg (ST910)Vehicle (ST-910)N = 6 anim als/cohort, IV adm inistration on Day 0HER2 status was determ ined with an earlier passage by IHC using SP3 Ab

ZW49 Significantly Improved Survival Compared to T-Exatecan Derivative and T-DM1 in HER2-High Breast Cancer Brain Metastasis Model

PDX M odel Tum or Type HER2 Expression (IHC)a

Tum or Status at Collection

Harvest site

CTG-0708 Breast High M etastatic Lung

CTG-0807 Breast M id M etastatic Lung

CTG-1017 Breast M id Prim ary Breast

CTG-1184 Breast M id Prim ary Breast

CTG-1167 Breast M id M etastatic Lym ph node

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CTG-0807

P-values were calculated using the log-rank test. P-values were corrected for m ultiple tests using the Holm -Bonferonni procedure.

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CTG-0708

a HER2 status was determ ined by the CRO on an earlier passage

• JIMT-1 model – n = 7 animals/cohort, IV administration on Day 0• CTG models – n = 6 animals/cohort, IV administration on Day 0, 14, 28, 42 (q2wx4)

ZW49 - 12 mg/kg T-Exatecan Derivative - 12 mg/kg T-DM1 - 12 mg/kgVehicle ZW49 - 6 mg/kg T-Exatecan Derivative - 6 mg/kgT-DM1 - 6 mg/kg

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Control Conjugate, 6 mg/kg qw

BT-474 Intracranial Overall Survival