EMERGING STRATEGIES FOR ENGINEERING MONOCLONAL ANTIBODIES WITH IMPROVED PK/PD. Douglas Sheridan, PhD Alexion Pharmaceuticals June 29 th, 2017

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1 EMERGING STRATEGIES FOR ENGINEERING MONOCLONAL ANTIBODIES WITH IMPROVED PK/PD Douglas Sheridan, PhD Alexion Pharmaceuticals June 29 th, 2017

2 DISCLOSURE Douglas Sheridan, Ph.D. Senior Director, Research Alexion Pharmaceuticals Inc. New Haven, CT I am a full time employee and shareholder of Alexion Pharmaceuticals Inc. Opinions expressed are my own and not necessarily those of Alexion Pharmaceuticals Inc. 2

3 ANTIBODIES AS THERAPEUTIC AGENTS Therapeutic Antibody Development Emil von Behring - Discovery of Humoral Immunity and passive vaccination -1 st Nobel Prize in Medicine, 1901 Paul Ehrlich Nobel Prize, Magische Kugel and Seitenkettentheorie Georges Köhler and César Milstein Nobel Prize, 1984 created hybridoma s to make the first monoclonal Abs Murine monoclonal IgG 3 muromonab-cd3 (Orthoclone OKT3), approved in 1986 for use in preventing kidney transplant

4 STATE OF THE ART Chimeric IgG Boulianne et al Nature, 1984 ~ 50% ADA response Humanized IgG Sir Gregory Winter Jones et al Nature, % ADA response murine human Fully human IgG Adalimumab first approved in 2002 by FDA Currently approved for the treatment of rheumatoid arthritis, psoriatic arthritis, 4 ankylosing spondylitis, Crohn's disease, moderate to severe chronic psoriasis and juvenile idiopathic arthritis Chimeric IgG 66% human Humanized IgG 95% human

5 INTERLEUKIN 6 PATHWAY IL-6 is a multifunctional cytokine that regulates: Immune response Hematopoiesis Inflammation Tumor proliferation Antagonism of the IL-6 signaling pathway has been clinically evaluated in: Rheumatoid Arthritis 5 Castleman Disease Giant Cell Arteritis Oncology Tanaka T. and Kishimoto T. Int J Biol Sci, 2012

6 INTERLEUKIN 6 PATHWAY The IL-6 / IL-6R complex is hexameric: Two IL-6 Two IL-6R Two gp130 IL-6R is active as both surface associated and soluble (shed) ectodomain 6 Kopf M. et al Nat Rev Drug Disc, 2010

7 ANTI-IL6R Tocilizumab (Chugai/Hoffmann La-Roche), humanized monoclonal IgG First in class anti-il6r Binds both soluble and membrane associated receptor Approved for: Castleman Disease (PMA 2005) Rheumatoid Arthritis (EMA 1009, FDA 2010) Juvenile Idiopathic Arthritis (FDA and EMA 2011) Sarilumab (Regeneron/Sanofi) 7 approved for RA by FDA

8 ANTI-IL6 Siltuximab, chimeric (mouse-human) monoclonal IgG Developed by Jaansen First in class anti-il6 Approved for: Multicentric Castleman Disease (FDA 2014) IV infusion, Q3W Failed to achieve objective response in: Phase II trial in Multiple Myeloma Phase II trial in Myelodysplastic Syndrome Phase I/II solid tumor trials, prostate cancer, renal cancer siltuxizumab (150 kda) murine human 8

9 OPPORTUNITIES FOR DIFFERENTIATING IMPROVEMENTS Dosing Regimen (less protein, less volume, less frequently) Extend duration of action (half-life of tocilizumab = 8-14 days) IV dosing for adult patients with Rheumatoid Arthritis: 4 8 mg/kg Q4W SC dosing for adult patients with Rheumatoid Arthritis: 0.9 cc, Q1W Q2W SC dosing for adult patients with Giant Cell Arteritis: 0.9 cc, Q1W Q2W IV dosing for juvenile patients with Idiopathic Arthritis: 8 12 mg/kg, Q2W Q4W Increase the potency Increase the concentration of binding sites Reduced TEAEs 9

10 SMART-Ig RECYCLING ANTIBODY - SA237 Re-engineered tocilizumab for improved PK Igawa T. et al Nature Biotechnology, 2010 (Chugai) Five residues in the variable domains were changed to histidine to weaken the affinity for IL-6R at ph < 6.0 A single amino acid substitution in CH3 (Asp434Ala) was made to increase FcRn-mediated recycling 10 tocilizumab (150 kda) SA-237 (150 kda)

11 ENHANCED FcRn RECYCLING IgG ph-dependent antigen binding: Histidine has a pka of ~ 6.0, therefore it has no charge in the blood (ph 7.4) and is positively charged in endosomes (ph < 6.0) Introducing a charge shift near the binding site accelerates dissociation of Ab:IL-6R complexes in endosomes Minimizes the impact of target-mediated clearance on the Ab Lessens the impact of Ab-mediated elevation of soluble IL-6R Enhanced affinity for FcRn: Increases probability of recycling to the vascular compartment 11 Confers a roughly 2x increase in τ½ Bern M. et al Journal of Controlled Release, 2015

12 PRECLINICAL PK/PD DATA ph-dependent binding to IL-6R reduced targetmediated clearance and elevation of soluble IL-6R These effects are additive with changes made to increase FcRn recycling Doubling the duration of effect from the same dose Enhanced FcRn recycling alone is not sufficient to 12 overcome target-mediated clearance Igawa T. et al Nat Biotech, 2010

13 CURRENT STATUS SA237 Partnered with Roche for Phase III development for Neuromyelitis Optica (NMO) Monthly SC dose Primary outcome measures: Time to first relapse Secondary outcome measures: Annualized relapse rate Primary outcome date Oct 2017 Study completion date Mar 2019 Note: Alexion is currently evaluating Soliris in a Phase III trial for NMO 13

14 NANOBODY - VOBARILIZUMAB Bispecific tandem V HH single domain antibody fragments: [anti-il- 6R:anti-HSA] Van Roy M. et al Arthritis Research & Therapy 2015 (Ablynx) V HH (12.5 kda) Llama-derived antibody fragments Camelids (and cartilaginous fishes) have evolved IgG isotypes with no light chain The variable region of these heavy chain-only antibodies (V HH ) can be expressed on its own as a small, simple and very well behaved antibody fragment But, such a tiny V HH fragment would have a serum half-life of just a few hours due to clearance via renal filtration IgG (150 kda) HcAb (75 kda) 14

15 TANDEM V HH : ENGINEERED FOR SC DOSING Small size More binding sites per mg Highly soluble More binding sites per ml Half life extension FcRn-mediated recycling by binding to albumin (τ½ ~ 3 weeks) High bioavailability and better tissue penetration Reduced risk of immunogenicity? High sequence identity between human and llama No Fc region No effector function capability No post-translational modifications Microbial production tocilizumab (150 kda) α-il-6r α-alb vobarilizumab (25 kda)

16 PRECLINICAL PK/PD DATA Half-life extension matched to albumin τ½ ~ 1 weeks in cynomolgus monkeys Target-mediated clearance observed (dose-dependent PK) Significant elevation of soluble IL-6R Effective suppression of free IL-6R Comparable to tocilizumab 16 Van Roy M. et al Arthritis Res Ther, 2015

17 Phase IIb Rheumatoid Arthritis Trial Results Efficacy: Failed to meet primary endpoint ACR20 score of 72-81% in TX arm vs 62% in PBO Comparable ACR20, ACR50 and ACR70 scores to tocilizumab in head to head monotherapy Significant benefit over SOC for low disease activity and remission scores in both monotherapy and combination therapy arms Dose regimen: High solubility enables extension of dose interval from Q1W (tocilizumab) to Q2W or Q4W Combination therapy (+MTX) 24 weeks (across studies* ) DAS28 CRP remission ACR70 vobarilizumab 49% 43% tocilizumab * 32% 20% adalimumab 23% 21% Monotherapy 12 weeks (head-to-head study) DAS28 CRP remission ACR70 vobarilizumab (225 mg Q2W, SC) 41% 21% tocilizumab (162 mg Q1Q, SC) 27% 23% Immunogenicity: 17 ADA observed in up to 31% of patients, but without effect on PK, efficacy or safety * tocilizumab: BREVACTA PhIII (sc) 162mg Q2W + MTX (Kivitz et al., Arthritis Care & Research, Nov 2014) adalimumab: Weinblatt et al, Arthritis & Rheumatology, Sept 2015

18 CURRENT STATUS Phase II trial in Systemic Lupus Erythematosus, ongoing Results expected in H Phase III trial in RA Preparing for end of Phase II regulatory meetings Planned start of Phase III by end of 2017 Abbvie declined to exercise option to partner (pursuing small molecule JAK1 inhibitor, ABT-494) 18

19 BIPARATOPIC BISPECIFIC ANTIBODY - BiSAb IgG-scFv fusion format targeting IL-6 (soluble ligand) Kasturirangan S. et al Journal of Biological Chemistry, 2017 (Medimmune) Biparatopic: Two different paratopes on the Ab, that bind the same antigen (at different epitopes) Increases potency in two ways: If the geometry is just right avidity for self associated Ag:Ab = super tight binding Binding to each epitope is independent therefore 99% of the 1% unbound is bound Sterically restricted from self-associating Can bind up to 4 IL-6 molecules α-il-6r(1) BiSAb (200 kda) α-il-6r(2) α-il-6r(1) α-il-6r(2)

20 INDUCED PHAGOCYTOSIS FcγR binding: If the Fc is capable of binding FcγRs, the avidity created with multiple linked Fcs can initiate phagocytosis of the complex by neutrophils, monocytes and macrophages Same clearance mechanism as that of a polyclonal humoral immune response Size Matters: Soluble complexes are actively cleared by Kupfer cells vis FcγR binding Larger, insoluble complexes can deposit in circulatory tissues, leading to a variety of diseases 20 Kasturirangan S. et al JBC, 2017

21 PRECLINICAL PK/PD DATA BiSAb:IL-6 complexes are cleared rapidly in mice Human IL-6 clears from circulation within 60 min IL-6 in complex with BiSAb clears more slowly, due to their size being too large for renal filtration BiSAb:IL-6 complexes are cleared by Kupffer cells Rapid clearance was not observed in FcγR knock out 21 mice Kasturirangan S. et al JBC, 2017

22 CURRENT STATUS Preclinical stage Likely won t develop, but others are using similar mechanisms What are clinical risks? No reported AEs in animals Potential to elicit immune response to drug and antigen Limiting PK? Multiple phases of complex formation in the dose cycle, due to changing ratios of Ab:Ag Potential for deposition in circulatory tissues? (See Immune Complex Mediated Diseases) 22

23 Spiess C. et al Mol Immunol, 2015 SUMMARY Engineers are clever Limited only by imagination Understanding of biology is still rate limiting Form follows function Nature is a fickle mistress Know the difference between what we could do and 23 what we should do

24 Thank You Questions? 24