Expanding the Horizon: Pioneering DART Bispecific Therapeutics in Areas Beyond Oncology

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Brendan Murphy
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1 Expanding the Horizon: Pioneering DART Bispecific Therapeutics in Areas Beyond Oncology Paul Moore - VP, Immunology and Cell Biology MacroGenics, Inc. 7 th Annual World Bispecific Conference Boston Sept 29, 216

DART Bispecific Platform Highly robust bispecific platform Multiple applications across different disease

Six DART molecules in clinical testing (1) Multiple pre-clinical programs advancing Significant validating

by collaboration partners (MGD11/duvortuxizumab by Janssen and PF-66718 by Pfizer).

The two antigen binding sites (shown by red dot circles) are separated from each other by approximately 3 Å

2 DART Bispecific Platform Highly robust bispecific platform Multiple applications across different disease areas Predictable manufacturability Long-term structural stability Ability to tailor half-life and valency Six DART molecules in clinical testing (1) Multiple pre-clinical programs advancing Significant validating DART collaborators Basic DART Crystallographic View (2) (1) Two clinical DART molecules are being developed by collaboration partners (MGD11/duvortuxizumab by Janssen and PF by Pfizer). (2) Crystallography of Pfizer s P-Cadherin x CD3 DART molecule. The two antigen binding sites (shown by red dot circles) are separated from each other by approximately 3 Å and are facing away from each other at an angle of approximately 9. Source: Root, et al., Antibodies 216, 5, 6; March 4, September 29, 216/Company Proprietary Information

3 DART: Designed for Broad Range of Modalities 3 September 29, 216/Company Proprietary Information

DART Formats Tailored for Different Applications

Monospecific Bispecific Bispecific Bispecific

Half-life Days to weeks Hours Days to weeks Days

4 DART Formats Tailored for Different Applications Construct mab DART DART DART Specificity Monospecific Bispecific Bispecific Bispecific Valency Bivalent Bivalent Bivalent Tetravalent Half-life Days to weeks Hours Days to weeks Days to weeks Examples margetuximab, enoblituzumab, MGA12 MGD6 MGD7, MGD9, MGD1, MGD11 (duvortuxizumab), MGD14, PF MGD13 4 September 29, 216/Company Proprietary Information

MGD1: Application of DART for Receptor Coligation Coligation of an activating receptor (CD79B; BCR component) with an inhibitory receptor (CD32B) on the same human B cell Designed to block B cell

5 MGD1: Application of DART for Receptor Coligation Coligation of an activating receptor (CD79B; BCR component) with an inhibitory receptor (CD32B) on the same human B cell Designed to block B cell activation in a nondepleting manner and to selectively target activated B cells Alternative to depletion-based strategies (Rituximab) or BLyS antagonists (Belimumab) Monovalent co-engagement of each target to favor avidity-driven binding selectivity to B cells 5 September 29, 216/Company Proprietary Information

6 CD32B and Its Involvement In Autoimmune Diseases Inhibitory regulator of both innate and adaptive immunity (only inhibitory FcgR) Expressed on leukocytes except for NK and T cells CD32B CD32B-KO mice fail to regulate humoral responses and develop lupus-like disease Checkpoint for B-cell activity maintaining humoral tolerance Allelic variant and expression level linked to autoimmune disease 6 September 29, 216/Company Proprietary Information

B Cell Normal Physiological Negative Feedback Loop Antigen B Cell Receptor (BCR) 3 CD79B 4 2 CD32B A hallmark of autoimmune disease is B cell reactivity and activation against Self antigens

7 B Cell Normal Physiological Negative Feedback Loop Antigen B Cell Receptor (BCR) 3 CD79B 4 2 CD32B A hallmark of autoimmune disease is B cell reactivity and activation against Self antigens Uncontrolled B cell activation 1 normally prevented by triggering of negative feedback loop Via engagement of CD32B (FcɣRIIb) 2 ITAM ITIM Triggered when BCR recognizes immunecomplexed antigen 3 and concomitant engagement of CD32B by the Fc domain of the complex bound IgG 4 Inhibition of the activation signal This shuts down expansion and activation of B cells reactive to self antigens 1 B-cell activation 7 September 29, 216/Company Proprietary Information

and inhibitory (CD32B) receptors through co-ligation BCR CD79B CD32B ITAM ITIM B-cell

8 Exploitation of Physiologic Inhibitory Pathway CD32B x CD79B DART-Mediated Negative Signaling Loop Antigen MGD1 recapitulates antigen driven proximity of activating (CD79B) and inhibitory (CD32B) receptors through co-ligation BCR CD79B CD32B ITAM ITIM B-cell activation Inhibition of the activation signal 8 September 29, 216/Company Proprietary Information

Anti-DART Anti-DART Anti-DART SSC CD19 Anti-DART

NK-cells CD19 T-cells CD14 CD16 CD3 EC 1 =.22±.

9 Anti-DART Anti-DART Anti-DART SSC CD19 Anti-DART MGD1: B-cell Specific Binding MGD1 Binds Selectively to Human B-cells B-cells Saturation Curve Binding to B-cells CD45 Monocytes CD3 NK-cells CD19 T-cells CD14 CD16 CD3 EC 1 =.22±.15 µg/ml EC 2 =.51±.22 μg/ml 9 September 29, 216/Company Proprietary Information

10 MGD1: Blocks B-cell Activation In Vitro Inhibition of BCR Activated Human B-cell Proliferation H -T d R (c p m ) H -T d R (c p m ) M G D 1 h Ig G 1 A n ti-c D 3 2 B m A b 5 M G D 1 A n ti-c D 7 9 B C o n tr o l D A R T A n ti-c D 3 2 B C o n tr o l D A R T C o n c e n tra tio n (n M ) C o n c e n tra tio n (n M ) Activity dependent on co-engagement of CD32B and CD79B 1 September 29, 216/Company Proprietary Information

. MGD1: Inhibition of Autoimmune Patient B-cell Activation PE-Texas Red-H: CD19 PE-Texas Red-H % In h ib itio n CD19 CD32B CD79B CD79B and CD32B expression on peripheral B-cells isolated from SLE

11 . MGD1: Inhibition of Autoimmune Patient B-cell Activation PE-Texas Red-H: CD19 PE-Texas Red-H % In h ib itio n CD19 CD32B CD79B CD79B and CD32B expression on peripheral B-cells isolated from SLE patient APC-H: ch2b6 APC-H PE-Texas Red-H: CD19 PE-Texas Red-H PE-H: CD79b PE-H 1 In a c t iv e S L E ( n = 6 ) MGD1 ex-vivo inhibition of B-cells isolated from SLE patients with active or inactive disease status A c t iv e S L E ( n = 8 ) 11 September 29, 216/Company Proprietary Information

12 h Ig M (E L IS A,n g /m L ) MGD1: Blocks B-cell Activation In Vivo Experiments performed in mice engrafted with human PBMC (Xenogeneic GVHD) h Ig M higg Inhibition of Ig Secretion p =. 1 higg (ELISA,ng/mL) p=.24 MGD 1 dosed IV: 1 µg/animal, q3d 2wk Serum Analyses: Day 7 P B S M G D 1 PBS MGD1 1 Inhibition of GVHD Cumulative Survival (%) Days MGD1 (5. mg/kg) MGD1 (1. mg/kg) Rituximab (5. mg/kg) PBS MGD 1 dosed IV: q4d 9 12 September 29, 216/Company Proprietary Information

R a tio MGD1: Prolonged PK and Absence of B-cell Depletion Dose escalation of MGD1 in cross-reactive non-human Primate TK prolonged and dose linear Prolonged B-cell occupancy Pre-Rx Day 28 MGD1

13 R a tio MGD1: Prolonged PK and Absence of B-cell Depletion Dose escalation of MGD1 in cross-reactive non-human Primate TK prolonged and dose linear Prolonged B-cell occupancy Pre-Rx Day 28 MGD1 Binding to B-cells post 1mg/kg dose B -c e ll/t -c e ll R a tio.6 No B-cell depletion V e h E n d D a y s 13 September 29, 216/Company Proprietary Information 13

14 MGD1: Inhibition of BCR Signaling Target Occupancy and Ex-vivo BCR Activation following 1 mg/kg MGD1 Target Occupancy Ex-vivo B-Cell Ca ++ Flux Assay Fluo-NW CD19 Fluo-NW Fluo-NW CD32B CD79B 15 GAH IgMµ- F(ab) 2 3 µg/ml Pre-Rx FL2-H: CD19 PE FL1-H: ch8b5 A488 FL2-H: CD19 PE FL4-H: CD79b APC 1 5 Pre-Rx Time (sec.) h 24 h FL2-H: CD19 PE FL2-H: CD19 PE FL1-H: ch8b5 A FL4-H: CD79b APB Time (sec.) Day 7 FL2-H: CD19 PE FL2-H: CD19 PE Day FL1-H: ch8b5 A FL4-H: CD79b APC September 29, 216/Company Proprietary Information Time (sec.)

15 MGD1: Phase 1A Study Design Enrolled healthy volunteers in six escalation cohorts Healthy volunteers represent homogeneous population to ascertain safety and pharmacodynamics effects of MGD1 Eight subjects to enroll at each dose cohort Six subjects were treated with MGD1 and two were treated with Placebo Staggered dosing at each dose cohort to assess safety & tolerability Randomized 6 subjects in double-blind manner after treating two sentinel subjects with MGD1 Subject 1: (MGD1) Subject 2: (MGD1) 24-hr Subjects 3-8: (4 MGD1; 2 Placebo) 24-hr R Dose Cohort MGD1 Dose (mg/kg) September 29, 216/Company Proprietary Information

16 MGD1: Phase 1A - Study Objectives Primary Objective Assess safety and tolerability of single dose of MGD1 in healthy adult subjects Secondary Objectives Evaluate single MGD1 dose pharmacokinetics Assess pharmacodynamics effects of MGD1 on humoral immune responses Evaluate potential anti-drug antibodies Exploratory Objectives Evaluate MGD1 binding to CD32B and CD79B on peripheral B cells Evaluate activation status of peripheral B cells and B-cell subsets Assess immune phenotype, including modulation of B-cell subsets Assess response of peripheral B cells to ex-vivo BCR stimulation 16 September 29, 216/Company Proprietary Information

17 C o n c e n t r a t i o n ( n g / m l ) % o f M a x B i n d i n g ( m e a n s e m ) MGD1: Human PK and Circulating B-cell Occupancy MGD1 Serum Levels B-cell Occupancy Days D a y s 6 h Days D a y s MGD1 Dosing: Placebo.1mg/kg.1mg/kg.3mg/kg 1 mg/kg 3 mg/kg 1 mg/kg MGD1 serum concentrations increase linearly with dose Half-life: ~8 days at 1mg/kg Maximum B-cell occupancy at doses 1 mg/kg Sustained receptor occupancy beyond one week at doses 1 mg/kg 17 September 29, 216/Company Proprietary Information

18 C e l l s / L ( m e a n s e m ) R a t i o ( m e a n s e m ) MGD1: No Evidence of B-cell Depletion Longitudinal Analyses of Peripheral Immune Cells Absolute B-cell Counts B/T Ratio h Days D a y s D a y s Placebo MGD1 Dosing:.1mg/kg.1mg/kg 1 mg/kg 3 mg/kg.3mg/kg 1 mg/kg 18 September 29, 216/Company Proprietary Information

19 S t i m u l a t e d B C e l l s / I o n o m y c i n ( m e a n s e m ) Treatment with MGD1 Inhibited B-Cell Activation R e la t i v e P e a k R e s p o n s e Relative Peak Response Placebo 1 mg/kg 3 mg/kg 1 mg/kg MGD1 Dosing Days s p<.1; p<.1 (Student s t-test compared to placebo) PBMCs from enrolled subjects collected longitudinally after MGD1 treatment Ca 2+ flux (hallmark of B-cell activation) induced ex vivo by B-cell receptor ligation using anti-igm Data normalized to maximum Ca 2+ permeability (maximum induction) via ionomycin Dose dependent B-cell inhibition demonstrated with increasing doses of MGD1 Inhibition sustained for several weeks at highest dose levels 19 September 29, 216/Company Proprietary Information

20 R e l a t i v e M F I ( % o f T i m e Z e r o, m e a n s e m ) % c h a n g e % c h a n g e R e l a t i v e M F I ( % o f T i m e Z e r o, m e a n s e m ) % c h a n g e MGD1 Modulated Cell Surface BCR and Serum Ig Levels CD27 - Naïve B Cells CD27 + Memory B Cells MGD1 Down-Regulation of Cell Surface Ig Expression migdm I g D Dose-dependent down modulation of cell surface BCR expression on both naïve and memory B cells Days D a y s miggm I g G Days a y s p<.5 (Paired t-test compared to baseline) MGD1 Modulation of Circulating Serum Ig Levels Serum S e r u m IIgG g G Days D a y s S e r u m I g M Placebo Serum IgM Days D a y s Serum S e r u m IIgA g A Days D a y s MGD1 Dosing: 1 mg/kg 3 mg/kg 1 mg/kg 2 September 29, 216/Company Proprietary Information

21 MGD1 Impacts Naïve & Mature B-cells Bone Marrow Periphery Stem Cell Pro B-cell Pre B-Cell Immature B-Cell Naïve B-Cell Mature B-Cell Cytoplasmic µ + Surface Surface Surface IgM + & IgD + IgM + & IgD + IgM+, IgG + & IgD + Memory B-Cell Surface IgG + & IgA + = CD32B = CD79B = Immunoglobulin Plasmablast Cytoplasmic IgM + Plasma Cell Cytoplasmic IgG + A single MGD1 dose: Modulates naïve and mature B-cell signal transduction via signaling blockade and/or down-regulation of surface Ig Decreases serum IgM levels, suggesting an impact on plasmablasts Lack of CD79B expression on plasma cells is consistent with no effect on other serum Ig 21 September 29, 216/Company Proprietary Information

22 M F I (m e a n S E M ) M F I (m e a n S E M ) MGD1 Mediates Reduction of B-cell CD4 Expression CD4 Expression C D 4 E x p r e s s i o n HLA-DR Expression H L A - D R E x p r e s s i o n h Days D a y s p<.5 (Paired t-test compared to baseline) 6 h 1 Placebo Days D a y s MGD1 Dosing: 1 mg/kg 3 mg/kg 1 mg/kg MGD1 has potential impact on B-cell : T-cell interactions Decreased cell surface expression of CD4, a B cell co-stimulatory molecule No effect on other cell surface markers observed HLA-DR (as shown), CD8/86, CD69, CD25 22 September 29, 216/Company Proprietary Information

23 Summary of Phase 1a Clinical Experience MGD1 is well tolerated as single dose up to 1 mg/kg in healthy subjects No B-cell activation or cytokine release No depletion of peripheral B cells Peripheral B-cells saturated at 1mg/kg dose levels with sustained receptor occupancy with increasing doses MGD1 down-modulated B-cell function at multiple levels Reduction in BCR-induced Ca2+ mobilization Decreased surface Ig expression both naïve and memory B-cells Decreased serum IgM levels, suggesting an impact on plasmablasts Data supports continued development of MGD1 in patients with autoimmune disorders 23 September 29, 216/Company Proprietary Information

24 DART Platform Applications in HIV Cure Challenge Proposed Strategy Current combination antiretroviral therapy (cart) cannot eradicate HIV infection Latency: the presence of integrated but transcriptionally quiet proviral DNA, primarily within central memory T cell population, makes the infected cells invisible to immune system Chronically infected individuals generally experience rapid viral rebound after cart interruption (usually within weeks) Latency-reversing agent (LRA) to reactivate HIV antigen expression Shock-and-Kill lysis Env Goal CD3 To reduce or eliminate HIV latent reservoirs T cells 24 September 29, 216/Company Proprietary Information

L U M (R L U ) T u m o r V o lu m e (m m 3 ) R a n d o m.

MGD11 (CD19 x CD3) 3 V e h ic le 2 5 C o n t r o l D A R T (.

1 9 1 m m 3 L a r g e r T u m o r G r o u p S m a lle r T u m o r G r o u p Anti-Tumor

reconstituted mice 1 8 6 4 2 Redirected T-cell Killing CD19+Raji + PBMC (E:T = 31:1) M G

Node, Spleen CD2 CD2 CD2 CD2 Profound B-cell Depletion in Lymphoid Organs (NHP) 1-1 1-8

25 L U M (R L U ) T u m o r V o lu m e (m m 3 ) R a n d o m. P B M C s T u m o r C e lls DART: Potent T-cell mediated Target Cell Elimination Example: MGD11 (CD19 x CD3) 3 V e h ic le 2 5 C o n t r o l D A R T (.5 m g / k g ) A v g T u m o r V o l m m 3 A v g T u m o r V o l m m 3 L a r g e r T u m o r G r o u p S m a lle r T u m o r G r o u p Anti-Tumor Activity R x Treatment of B-cell lymphoma (HBL-2) in human T-cell reconstituted mice Redirected T-cell Killing CD19+Raji + PBMC (E:T = 31:1) M G D 1 1 C D 1 9 -B it E C o n tro l M P 3 D A R T Inguinal Lymph Node Mandibular Lymph Node, Spleen CD2 CD2 CD2 CD2 Profound B-cell Depletion in Lymphoid Organs (NHP) C o n c e n tra tio n (n M ) Liu et al., 216 Clinical Cancer Research (In press) Control MGD11 25 September 29, 216/Company Proprietary Information 25

ADCC-mediating A32 7B2 Adapted from Euler Front Immunol 212 Variant Env structures (legitimate targets on infected cells) Mature

26 Broadly Reactive Anti-Env Antibodies and Their Targets Mature Env trimer V1-V2 loop PGT145 CD4-binding site VRC1 C1-C4 (gp12 cluster A) A32 Glycan-V3 loop PGT121 gp41 cluster I 7B2 Broadly Neutralizing PGT121 PGT145 VRC1 1E8 gp41 MPER 1E8 Non-Neutralizing, ADCC-mediating A32 7B2 Adapted from Euler Front Immunol 212 Variant Env structures (legitimate targets on infected cells) Mature trimer Uncleaved gp16 trimer gp41 stump (gp12 shedding) Alternate trimer gp12/gp41 monomers 26 September 29, 216/Company Proprietary Information

27 HIV X CD3 Molecules Mediate Potent CTL Activity Env+ Jurkat-522 F/Y cells (targets), pan-t-cells (effectors), cytolysis by LDH release assay EC5 ~15 pg/ml (~3 pm) Sung et al. 215 J Clin Invest 27 September 29, 216/Company Proprietary Information

28 DART Molecule-mediated CTL Activity Against HIV-Infected CD4+ Cells Resting CD4+ T cells infected with HIV-1; CD8+ T cells (E:T 2:1); assay p24+ CD4+ cells HIV-1 RW/92/8 (subtype A) HIV-1 BaL (subtype B) HIV-1 IN/93/95 (subtype C) High potency HIV DARTs A32, 7B2, PGT121, PGT145 Low potency HIV DARTs VRC1, 1E September 29, 216/Company Proprietary Information Sloan et al. 215 PLOS Pathogens

29 HIV Clearance in Resting CD4 Cells Reactivated By LRA HIV pt on ART PBMC Resting CD4 + cells, culture with ARVs (24h) CD8 + cells + VOR (6h) ± DART (24-96h) E:T = 1:1 Allogeneic HIV - donor cells to amplify virus (15 days) p24+ wells (QVOA) HIV DART molecule-mediated virus clearance in 4 of 4 patients (longer time needed for Pt 795) September 29, 216/Company Proprietary Information Sung et al. 215 J Clin Invest

30 MGD14: HIV x CD3 DART Candidate Targeted Indication Development Partner Humanized HIV x CD3 Fc-bearing DART (extended PK) HIV arm based on a broadly reactive, ADCC-mediating, nonneutralizing anti-env antibody Elimination of latent HIV infection in combination with latencyreversing agents and anti-retroviral therapy (ART) Preclinical activities ongoing Initial GMP production completed IND targeted for 1H:217 MacroGenics retains worldwide commercial rights Funded through NIAID (NIH) contract awarded 9/15/15 In collaboration with Duke/UNC 3 September 29, 216/Company Proprietary Information

31 MG Pipeline of Product Candidates Clinical-stage programs Program (Target) Indication Pre-IND Phase 1 Phase 2 Phase 3 Partner Our Commercial Rights ONCOLOGY margetuximab (HER2) Breast (HER2+) SOPHIA Green Cross Worldwide, except Breast (low HER2) South Korea Gastric (+pembrolizumab) enoblituzumab (B7-H3) Solid Tumors (mono.) Worldwide Solid Tumors (+ipi.) Solid Tumors (+pembro.) MGD6 (CD123 x CD3) AML/MDS Servier North America, Japan, South Korea, India MGD7 (gpa33 x CD3) Colorectal MGD11 (CD19 x CD3) B-cell Malignancies Janssen U.S. Co-promote MGD9 (B7-H3 x CD3) Solid Tumors Worldwide MGA12 Solid Tumors/Heme Worldwide MGD13 (PD-1 x LAG-3) Solid Tumors/Heme Worldwide AUTOIMMUNE & INFECTIOUS DISEASES teplizumab (CD3) Type 1 Diabetes Prev. NIDDK/NIH Worldwide MGD1 (CD32B x CD79B) Autoimmune Disorders Worldwide MGD14 (HIV x CD3) HIV NIAID/NIH Worldwide MacroGenics has option to fund late-stage development in exchange for U.S. and Canada profit share. DART mab 31 September 29, 216/Company Proprietary Information

What is the place of the monoclonal antibodies in the clinic?

What is the place of the monoclonal antibodies in the clinic? Dr Julià Blanco 2018/04/26 DISCLOSURE AlbaJuna Therapeutics, S.L. ANTIBODIES IN HIV INFECTION. ANTIVIRAL (NEUTRALIZING) ACTIVITY env THE BROADLY