29 We incorporated the following design features into KSI-501: • Binds with high affinity to the most abundant isoforms of VEGF • Engineered to remove a protease hotspot to prevent cleavage in Chinese Hamster Ovary, or CHO, mammalian expression systems, which may improve potency and formulation stability Design Feature: KSI-501’s anti-IL-6 domain • Affinity matured, humanized anti-IL-6 IgG1 that binds with high affinity to IL-6 and inhibits binding of IL-6 to its cognate receptor • IgG1 Fc domain engineered to reduce immune effector functions Design Feature: KSI-501’s phosphorylcholine-based ABC Platform • Ultra-high molecular weight of 1,000,000 Daltons for improved ocular pharmacokinetics • Same IgG1 framework sequences and same phosphorylcholine-based biopolymer as KSI-301 and other ABC Platform-derived product candidates to simplify manufacturing and product development • Other benefits of the ABC Platform such as enhanced tissue access to key ocular tissues and bioconjugate stability Note that the in vitro data shown below are generated using the TAF (protein) of KSI-501, without conjugation to our ABC biopolymer. Results using KSI-501 may be different, but experience with a structurally similar prior molecule, KSI-201, has shown that these individual components, i.e. trap antibody fusion protein and biopolymer, can function together simultaneously as a dual inhibitor bioconjugate. Prior experiences with bioconjugates KSI-201 and KSI-301 have also demonstrated that the biopolymer portion does not interfere with the bioactivity of the protein portion. Affinity and concurrent binding to VEGF and IL-6 Preclinical studies indicate that the TAF portion of KSI-501 binds with high affinity to both VEGF and IL-6, as measured by SPR analysis (Table). Importantly, binding of each molecule has no effect on the binding of the other, and KSI- 501 can bind to both molecules as shown below. Thus, we believe our dual inhibitor can simultaneously inhibit both of its targets with high potency. Table: Binding kinetics of TAF portion of KSI-501 to huVEGF-A165 or IL-6 by SPR analysis. Molecule Kon (M) Koff (M) KD (pM) IL-6............................................................................................................ 3.72x106 4.06x10-4 109 VEGF-A165.............................................................................................. 1.07x107 1.63x10-4 15.2 Figure: TAF of KSI-501 simultaneously binds to IL-6 and VEGF by sandwich ELISA, which only shows a signal if a compound binds to both IL-6 and VEGF concurrently. 0 1 2 3 log[Antibody] nM OD450nm KSI-501 protein Eylea Anti-IL6 2 0 -2 -4