ISB 1442 Preclinical Data Summary: First-in-Class CD38 and CD47 Bispecific Antibody Innate Cell Modulator for Relapsed / Refractory Multiple Myeloma

ISB 1442 Preclinical Data Summary: First-in-Class CD38 and CD47 Bispecific Antibody Innate Cell Modulator for Relapsed / Refractory Multiple Myeloma Stefano Sammicheli, et al 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational I. ASH 2021 DO NOT COPY OR DISTRIBUTE High Unmet Medical Need Remains in Patients with Relapsed / Refractory Multiple Myeloma, Despite Recent Advances in Treatment • Significant unmet medical need exists in triple refractory patients that have progressed following treatment with proteasome inhibitors, IMiD and anti-CD38 monoclonal antibodies1 o ORR with subsequent therapies is 31%​ o Median OS is 9.3 months and median PFS is 3.4 months​ • Several primary and acquired known tumor resistance mechanisms are implicated in relapse following treatment with CD38-targeted antibodies2 o Decreased CD38 cell surface density​ o Resistance to Complement Dependent Cytotoxicity (increased complement regulatory protein expression)​ • Resistance to phagocytosis (CD47 “do not eat me” signal overexpression)​ o New therapies with more complete and durable responses are needed​ 2 1 Gandhi UH et al. Leukemia 2019; 33: 2266–75. 2 Saltarella I. et al. CELLS 2020 ICHNOS SCIENCES ISB 1442 2021.12.10 DO NOT COPY OR DISTRIBUTE FIRST-IN-CLASS ISB 1442 KEY ATTRIBUTES​ • Two high-affinity Fab arms drive binding to distinct CD38 epitopes on tumor cells o None of the epitopes show functional competition with daratumumab 3 BEAT® 2.0 (Bispecific Engagement by Antibodies based on the T-cell receptor) 2+1 BISPECIFIC ANTIBODY CD47 Low affinity CD38 High affinity CD38 High affinity Fc enhancing mutations • One Fab arm blocking CD47-SIRPα binding in cis on tumor cells to enhance ADCP o Increased tumor phagocytosis o Reduced potential for antigen sink with lower- affinity Fab binding to ubiquitous CD47 • Potent ADCC and CDC based on o Optimized affinity, epitope, architecture/avidity and Fc engineering​ • Optimized tolerability o Low potential for hemagglutination, platelet aggregation​ ICHNOS SCIENCES ISB 1442 2021.12.10 ISB 1442 Redirects Myeloid Cells to CD38+ Tumors Using Ichnos’ Proprietary Beat® 2.0 Platform BEAT interface ADCP: Antibody-Dependent Cell Phagocytosis, ADCC: Antibody-Dependent Cell Cytotoxicity, CDC: Complement Dependent Cytotoxicity Data presented at American Society of Hematology 2021 Annual Meeting. Author, Stefano Sammicheli, et. al DO NOT COPY OR DISTRIBUTE CD38 CD47 180’000 60’000 10-3 10-2 10-1 100 101 102 103-20 0 20 40 60 80 100 120 Antibody concentration (nM) CD47/SIRPa inhibition (%) anti-CD47 mAb (5F9) ISB 1442 ISB 1442 Efficiently Blocks CD47/SIRPα Interactions and Induces Enhanced Phagocytosis of CD38 Low-Expressing Tumor Cells Compared to Daratumumab CD38high (Daudi) ISB 1442 induces comparable blockade of CD47/SIRPα interactions to that of clinical benchmark 5F9 (bivalent high affinity anti-CD47 fab arms equivalent to magrolimab). Statistics: Tukey’s multiple comparison test. CD38 CD47 180’000 60’000 CD38high (Daudi) 10-510-410-310-210-1100 101 102 103 0 20 40 60 80 Antibody concentration (nM) Phagocytosis index ISB 1442 Daratumumab anti-CD47 mAb (5F9) CD38 CD47 5’000 210’000 CD38low (KMS-12-BM) 9nM 5F9 900nM ISB 1442 While phagocytosis of CD38high expressing tumor is comparable to that induced by benchmarks, ISB 1442 enables a significant increase in maximal phagocytosis of KMS- 12-BM (CD38low) tumor cells relative to that of daratumumab. 10-610-510-410-310-210-1100 101 102 0 20 40 60 80 Antibody concentration (nM) Phagocytosis index P<0.005 NS 4ICHNOS SCIENCES ISB 1442 2021.12.10 Data presented at American Society of Hematology 2021 Annual Meeting. Author, Stefano Sammicheli, et. al DO NOT COPY OR DISTRIBUTE 100 101 102 103-20 0 20 40 60 80 100 120 Antibody concentration (nM) Specific killing (%) Daratumumab anti-CD47 mAb (5F9) ISB 1442 Is. Control P<0.0005 CD38 CD47 180’000 60’000 ISB 1442 Shows Higher CDC and ADCC Activities Relative to Clinical Benchmark Daratumumab Complement Dependent Cell Cytotoxicity (CDC) CD38high (Daudi) Antibody Dependent Cell Cytotoxicity (ADCC) CD38 CD47 190’000 125’000 CD38high (Raji) CD38 CD47 31’000 94’000 CD38low-int (NCI-H929) 10-4 10-3 10-2 10-1 100 101-20 0 20 40 60 80 100 120 Antibody concentration (nM) Specific killing (%) ISB 1442 anti-CD47 mAb (5F9) Daratumumab Is. Control 10-4 10-3 10-2 10-1 100 101 0 20 40 60 Antibody concentration (nM) Specific killing (%) NCI-H929 EC50 (nM) SD P-value ISB 1442 0.001 0.001 <0.05Daratumumab 0.012 0.012 • ISB 1442 shows higher CDC of tumor cells compared to clinical benchmark daratumumab • Results with CD38low tumor cells are not shown because these cells express a high level of complement inhibitory proteins1 and CD38 density is not sufficient to enable CDC • ISB 1442 induces comparable killing of CD38high expressing tumor cells to daratumumab • In NCI-H929 tumor cells, ISB 1442 shows a lower EC50 compared to daratumumab, suggesting a higher potency in the context of CD38low expression 1 Nijhof I.S. et al. Blood 2016. 5F9 is expected to induce low/absent CDC given its IgG4 construct. Statistics: Tukey’s multiple comparison test. EC50: Half Maximal Effective Concentration, SD: Standard deviations 5ICHNOS SCIENCES ISB 1442 2021.12.10 Data presented at American Society of Hematology 2021 Annual Meeting. Author, Stefano Sammicheli, et. al DO NOT COPY OR DISTRIBUTE ISB 1442 Shows Superior Tumor Cell Killing In a MMoAK Assay Compared To Daratumumab and 5F9 Clinical Benchmarks and Their Combination, and Is Not Impacted by CD38 or CD47 Antigen Sink Multiple Mode of Action of Killing (MMoAK) ISB 1442 Against Benchmarks Anti- CD47 (5F9) and Daratumumab A ISB 1442 Against Anti-CD47 (5F9) + Daratumumab Combination C 10-4 10-2 100 102 104 -20 0 20 40 60 80 100% Specific killing ISB 1442 Daratumumab anti-CD47 mAb (5F9) Antibody concentration (nM) P<0.05 P<0.000 5 P<0.05 10-4 10-2 100 102 104 -20 0 20 40 60 80 Antibody concentration (nM) % Specific killing ISB 1442 Daratumumab + anti-CD47 mAb (5F9)* ISB 1442 Potency in the Presence of CD38 and CD47 Antigen Sink B 0 20 40 60 Maximum Killing (%) NSISB 1442 + RBC 30 40 50 60 70 80 Maximum Killing (%) NS + sCD38 ISB 1442 Statistics: Tukey’s multiple comparison test. CD38low-int (NCI-H929) CD38 CD47 31’000 94’000 In Vitro Potency in MMoAK Assay A. ISB 1442 induces higher killing of tumor cells in MMoAK compared to benchmarks daratumumab and anti-CD47 (5F9) B. ISB 1442 potency in vitro is not impacted by presence of CD38 and CD47 antigen sink C. ISB 1442 induces higher maximal killing of tumor cells compared to the combination of daratumumab and anti-CD47 (5F9) 6ICHNOS SCIENCES ISB 1442 2021.12.10 Data presented at American Society of Hematology 2021 Annual Meeting. Author, Stefano Sammicheli, et. al DO NOT COPY OR DISTRIBUTE ISB 1442 Shows a More Favorable On-Target Specificity, with Reduced Binding on RBC, Hemagglutination and RBC Depletion Compared to Anti-CD47 Monoclonal 5F9 Antibody ISB 1442 low affinity anti-CD47 Fab arm allows avidity induction binding to CD47 only upon CD38 targeting, thereby avoiding on target-off tumor binding to CD47 on RBC Binding to Red Blood Cells (RBC) Statistics: 2-way ANOVA with multiple comparisons. P values: 0.1223 (ns), 0.0332(*), 0.0021(**), 0.0002(***), <0.0001(****). RBC Depletion Statistics: 2-way ANOVA with multiple comparisons. P values: 0.00990 (ns), 0.0140 (*), 0.0022(**), <0.0001(****). 100 101 102 103 0 5×102 1×103 1.5×103 2×103 5×103 1×104 1.5×104 Antibody concentration (nM) Antibody binding (GeoRFI) Anti-CD47 mAb (5F9) ISB 1442 ** * ** *** **** **** 100 101 102 103 104 0 20 40 60 80 100 Antibody concentration (nM) % RBC vs baseline ISB 1442 anti-CD47 mAb (5F9) * ** **** **** ****ns • ISB 1442 shows limited binding to RBC compared to anti-CD47 5F9 mAb • ISB 1442 does not deplete RBC in vitro, unlike prominent depletion observed with anti-CD47 5F9 mAb 10-4 10-2 100 102 104 0 1 2 3 4 5 Antibody concentration (nM) Coombs Score ISB 1442 anti-CD47 mAb (5F9) Hemagglutination (Coombs Assay) Statistics: Tukey’s multiple comparison test EC50: Half Maximal Effective Concentration, SD: Standard deviations EC50 (nM) SD P-value ISB1442 0.34 0.169 <0.0001 5F9 0.01 0.004 • ISB 1442 shows higher EC50 of hemagglutination compared to that induced by anti-CD47 5F9 mAb 7ICHNOS SCIENCES ISB 1442 2021.12.10 Data presented at American Society of Hematology 2021 Annual Meeting. Author, Stefano Sammicheli, et. al DO NOT COPY OR DISTRIBUTE ISB 1442 Shows Improved Tumor Growth Inhibition In Preclinical Model Compared To Daratumumab • 10 million Raji cells were implanted subcutaneously into CB17/SCID mice. • Animals were randomized when tumor volume reached ~100 mm3. Doses: ISB 1442 and 5F9 (anti CD47) dosed IV QW at 10 mg/kg, Daratumumab dosed IV BIW at 16 mg/kg. Statistics: 1-way ANOVA w. Tukey post hoc testing. Raji model • ISB 1442 shows higher tumor growth inhibition than daratumumab • ISB 1442 shows comparable tumor control to that induced by high affinity anti-CD47 mAb (5F9) • High efficacy with anti-CD47 bivalent 5F9 mAb is expected in this mouse model because anti-tumor immunity is driven by innate effectors with a strong bias to the CD47-SIRPα axis2 5 8 12 15 19 22 26 29 33 36 0 500 1000 1500 Days after xenograft Tumors Volume (mm3) PBS ISB 1442 anti-CD47 mAb (5F9) Daratumumab First Dose *** ** P<0.01 P<0.001 8ICHNOS SCIENCES ISB 1442 2021.12.10 Data presented at American Society of Hematology 2021 Annual Meeting. Author, Stefano Sammicheli, et. al DO NOT COPY OR DISTRIBUTE 92021.12.10 Conclusions 01 ISB 1442 represents a novel approach for the treatment of CD38+ tumors by co-targeting CD38 and CD47 in a 2+1 biparatopic bispecific antibody 04 ISB 1442 shows low on-target off-tumor binding compared to anti-CD47 mAb (5F9), potentially resulting in a better therapeutic index than anti-CD47 bivalent mAbs 02 ISB 1442 shows higher potency in vitro relative to daratumumab in CD38high/low tumor models as measured by multiple antibody-dependent mechanisms of action 05 Enrollment in the first-in-human ISB 1442 trial is expected to start in mid-2022 03 ISB 1442 shows higher tumor growth inhibition than daratumumab in CD38high preclinical models ICHNOS SCIENCES ISB 1442 Data presented at American Society of Hematology 2021 Annual Meeting. Author, Stefano Sammicheli, et. al THANK YOU

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