Preclinical Evaluation of MCLA-129: a Bispecific Antibody Targeting C-MET and EGFR

#LB-C07 Preclinical evaluation of MCLA-129: a bispecific antibody targeting c-MET and EGFR

1 2,3 2,3 1 1 1 1 1 1 AACR-NCI-EORTC Meeting 2019 Cecile Geuijen , Mario di Matteo , Sarah Trusso Cafarello , Tristan Gallenne , Roy Nijhuis , Therese Visser , Willem Bartelink , Carina Bartelink-Clements , Vanessa Zondag-van der Zande , Boston, MA, USA Eric Rovers1, Karin de Cortie1, Linda Kaldenberg-Hendriks1, Berina Eppink1, Rinse Klooster1, John de Kruif1, Massimiliano Mazzone2,3, Mark Throsby1 October 26-30, 2019 1Merus N.V. Utrecht, The Netherlands; 2Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium; 3Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Belgium.

BACKGROUND & RATIONALE MCLA-129 SELECTION & CHARACTERISTICS MCLA-129 INHIBITS TKI RESISTANT NSCLC MCLA-129 REVERSES ACQUIRED TKI RESISTANCE

• HCC827 tumor cells were engrafted into A B pMET • EGFR and c-MET activate the same signalling • Specific combinations of c-MET and 20

mHGF immunodeficient NOD SCID gamma (NSG) ) a

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pathways to drive proliferation, survival and e r

EGFR Fab arms in the Biclonics® e r

human hepatocyte growth factor knock-in a

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hHGFki

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invasion. format result in either potent + 10

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(hHGFki) mice, that express human HGF in t

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hHGF M antagonistic or agonistic activity. place of endogenous mouse HGF (NSG- p 5 • MET/HGF amplification has a potential role in % hHGFki mice, stk#014553)3. ( resistance to EGFR targeted treatment (e.g. • MCLA-129 selected from a panel of 8 0 1 0h 4h 24h NSCLC, GBM) . Biclonics® based on potency of c-MET • The mice were treated with: Erlotinib (6 inhibition. pEGFR • Proliferation inhibition (%) mg/kg) once daily (QD) and antibodies/ In NSCLC, resistance to TKI inhibition of mutant Proliferation inhibition (%) 3 0 0 ** 0 0 5 2 1001 505 0 0 -50-

EGFR is associated with c-MET signalling . • MCLA-129 competes with the ligand antibodies combinations (25mg/kg) weekly. )

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0 binding domains of EGFR and c-MET. l

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• In patients treated with EGFR-TKIs, high a

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circulating HGF predicted poor prognosis. o 1 A 1

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% p

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A 1 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 1 1 1 1 1 1 1 1 1 1 2 B B B B B B B B B

c-METxEGFRB B B B B B B B B B B BICLONICS® REVERSE HGF RESISTANCE C ® THE BICLONICS PLATFORM Erlo->Erlo Erlo->Erlo MCLA-129 4hr Erlo->Erlo MCLA-129 24hr HCC827 Cells

Mock α-EGFR α-c-MET HCC827 cells Cetux + 5D5* + Erlotinib 150

MCLA-129** + Erlotinib MET )

Common Light Chain % ( 100

IgG Format n o

for ‘unforced’, natural i * t

a PIMO

for efficient manufacturing r PIMO PIMO e

pairing with 2 different f i l 50

and predictable in vivo o PIMO: pimonidazole staining (representing hypoxic regions within the tumor) r

heavy chains P behavior (A) Tumor volume (circles), (B) % of phosphorylated receptors in tumor sections, and (C) hypoxic tumor area 0 *variant _ HGF EGF HGF + EGF in mice sacrificed: 2hr post Erlotinib 6mg/kg QD treatment (0h) or 4h and 24h after MCLA-129 + EGFR Electrostatic attraction *MetMab analog administration and 2hr after Erlotinib 6mg/kg QD treatment. *p<0.05. Fc Modifications **variant to efficiently drive PC-9 cells for improved functionality 150 * formation of Biclonics®

(ADCC or silencing) ) *MetMab analog • hHGFKi mice engrafted with HCC827 tumors and treated daily with Erlotinib exhibited rapid

% ( 100 3

n tumor growth after a period of control; at day 51 (tumors >500 mm ) mice were

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• Combinationr of EGF and HGF reverses TKI inhibition in both NSCLC cell lines. randomized to continue Erlotinib treatment alone or in combination with MCLA-129.

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• MCLAP -129 restores sensitivity of NSCLC cell lines to Erlotinib. • In mice receiving the combination of Erlotinib and MCLA-129 tumor volume decreased UNBIASED SCREENING dramatically (A) and was associated with inhibition of EGFR and c-MET phosphorylation (B) • MCLA0 -129 inhibits HGF and EGF induced phosphorylation of receptors. HGF EGF HGF + EGF and a decrease in the hypoxic tumor area (C). • MCLA-129 is more potent in HCC827 cells than Cetuximab + MetMab analog (5D5).

150 Potent antagonists

n KEY FINDINGS AND CONCLUSIONS

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t Cetuximab + MetMab analog INFLUENCE OF RECEPTOR DENSITY ON ADCC i

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n i • MCLA-129 is a high-affinity, ADCC-enhanced cLC Biclonics® targeting human EGFR and c-MET. h BxPC-3 cells BxPC-3 cells t 50 • Afucosylation of MCLA-

w Potent agonists Low Affinity High Affinity o r 40000

g • MCLA-129 was selected from a large panel of bispecific antibodies using an unbiased screen 129 is required for ADCC

MCLA-129 ADCC enhanced 120000 MCLA-129 ADCC enhanced

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0 U MCLA-129 WT MCLA-129 WT

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s • Treatment with MCLA-129 led to sustained HCC827 growth inhibition both alone or when

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e e a -50 20000 combined with Erlotinib and this activity was maintained after treatment was stopped. • MCLA-129 can overcome HGF mediated Erlotinib resistance in NSCLC cell lines in vitro.

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Normalized % growth inhibition % growth Normalized

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i 40000 EGFR and c-MET, i.e. m

437 c-MET x EGFR Biclonics® m • Inhibition of tumor growth induced by MCLA-129 was greater than that induced by the anti- • MCLA-129 shows tumor shrinkage in the Erlotinib resistant HCC827 in immunocompromised u

-100 u L L 20000 BxPC-3, are preferentially NSG-hHGFki mice by inhibiting phosphorylation of EGFR and c-MET. 0 0 c-MET benchmark antibody Emibetuzumab. 0.0001 0.001 0.01 0.1 1 10 0.0001 0.001 0.01 0.1 1 10 targeted by ADCC. IgG conc (log[g/ml]) IgG conc (log[g/ml]) • The combination treatment of MCLA-129 with Erlotinib fully inhibited HCC827 tumor growth • These preclinical data suggest MCLA-129 could benefit NSCLC patients that become resistant up to 94 days of treatment in contrast to all other treatments. to EGFR targeted therapies and warrants clinical evaluation.

References Disclosures Scan the QR code for an electronic copy of the poster. 1. Tsuji et al. Oncotarget. 2017;8(42):71805-71816 Cecile Geuijen, Tristan Gallenne, Roy Nijhuis, Therese Visser, Willem Bartelink, Carina Bartelink-Clements, Vanessa Zondag-van der Zande, Eric Rovers, Karin de Cortie, Linda Kaldenberg-Hendriks, Berina Eppink, Rinse Klooster, John de Kruif, Mark Throsby: These materials are for personal use only and may not be 2. Engelman et al. Science. 2007;316(5827):1039-1043. Employment and stock ownership – Merus NV reproduced without permission. 3. Goyama et al. Blood. 2015;125(17):2630-2640. This study was sponsored by Merus NV (Utrecht, the Netherlands)