Slides
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The development story of REGULGENTTM Antibody Biology Group, Core Research Laboratory Hikaru Miyagi
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© Kyowa Kirin Co., Ltd.2 Why Bi-Specific Antibodies? Clinical trials of multispecific antibodies have surged over the past decade Monospecific antibody (IgG) ⚫ Depletion of target antigens ⚫ Limitations with a single antigen (efficacy, resistance, multiple factors) ⚫ Target Selectivity and Toxicity Bispecific antibody Limits of conventional monospecific antibodies Antigen A Antigen A Antigen A Antigen A Antigen B Antigen B
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© Kyowa Kirin Co., Ltd.3 Analysis by Drug Status × Mechanism Drug Status Total number of items Mechanism Number of items What can be read Approved 22 T cell engager 12 CD3 engagers dominate marketed products Two ligand inactivation 6 dual blockade type is also established Two ligand recruitment 3 ligand bridging type also partially exists Other 1 Other Special Formats Clinical 613 Two ligand recruitment 232 Immune modulation is the largest pipeline category T cell engager 210 TCE remains the central modality Two ligand inactivation 101 Checkpoint/ligand dual blockade expanding Other 70 trispecific, fusion, etc. Table created by the presenter based on Beacon Globally, many MOAs* (relatively simple MOAs) have been developed Mechanism of Bispe's Antibody *TCE: T cell engager (molecule that bridges T cells with target cells) / MOA: Mechanism of Action
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© Kyowa Kirin Co., Ltd.4 About REGULGENTTM N- and C-terminal bivalent forms ⚫ Applicable to diverse mechanisms of action Low-immunogenicity structure ⚫ Common L-chain (*) + natural IgG sequences ⚫ Uniform: no unwanted H/L pairings ⚫ IgG-like properties and kinetics Stable, easy-to-handle production ⚫ IgG-equivalent productivity ⚫ Uses conventional antibody processes A unique bispecific technology built on our antibody research * * N-terminal type * * C-terminal type Antigen A Binding Domain (Usually IgG structure) Common L-chain Common L-chain Common light chains prevent light/heavy chain mispairing Antigen B Binding Domain Characteristics of REGULGENTTM
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© Kyowa Kirin Co., Ltd.5 More chain types per molecule Mispairing (impurities) occurs Decline in production volume Decline in purification efficiency Cost increase Increasing technical hurdles Trispecifics* are emerging globally. For complex molecules and CMC, fewer chain types are better! Manufacturing Challenges of Bispecific Antibodies *Trispecific: an antibody that binds three targets simultaneously Compatible with the same manufacturing method as monoclonal antibodies!
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© Kyowa Kirin Co., Ltd.6 Kyowa Kirin was ahead of the curve in developing fully human antibody-producing mice ⚫ Developed HAC* technology that introduces human antibody genes into mice ⚫ By producing antibodies similar to those in humans, it is expected that immunogenicity can be reduced. ⚫ The potential for antibody drugs has greatly expanded, such as the ability to provide antibodies that can be continuously administered Fully human antibody Animals Built on Kyowa Kirin's R&D expertise A A B B *Human Artificial Chromosome Could we deliberately obtain antibodies sharing the same light chain? Antibodies recognizing different targets happened to share the same light chain REGULGENTTM was inspired by Kyowa Kirin's original technology
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© Kyowa Kirin Co., Ltd.7 Efficacy Toxicity Efficacy Toxicity Signal activation Signal activation Target A Target B Bioactive substance REGULGENT antibodies Standard antibody REGULGENT antibody Previously impossible drug concepts become possible! No CMC concerns, so medicines reach patients faster Previously undruggable toxic targets Mimicking complex -forming ligands The value REGULGENTTM offers
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© Kyowa Kirin Co., Ltd.8 (modified）Wajant Cancers 2019 Jul 7; 11(7):954. Licensed under CC-BY 4.0 ⚫ Belonging to the TNF receptor family ⚫ Forming a trimer to induce the death signal ⚫ It is widely expressed in both normal cells and solid tumors, but cancer cells are more susceptible ⚫ Expected as a target for antibody drugs ⚫ Several TRAIL-R2 drugs have entered clinical trials but have been discontinued due to insufficient efficacy or liver toxicity Needed: a strong death signal only in cancer cells TRAIL-R2 (aka: DR5, Death Receptor 5, TNFRSF10B) is A cell surface receptor that binds to the apoptosis-inducing ligand (TRAIL) to induce cell death (apoptosis) Application Example of REGULGENTTM: TRAIL-R2 Bispecific
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© Kyowa Kirin Co., Ltd.9 TRAIL-R2 PSMA PSMA: Prostate specific membrane antigen PSMA TRAIL-R2 PSMA arm targets cancer cells; TRAIL-R2 arm triggers cell death Induce cell death target antigen TRAIL-R2 Anti -TRAIL -R2 antibody Anti -PSMA* antibodies Prostate cancer, etc. target antigen PSMA Anti -PSMA/TRAIL -R2 antibody Cancer Target Antigen x TRAIL-R2 Bispecific Antibody
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© Kyowa Kirin Co., Ltd.10 Productivity comparable to IgG 0 100 200 300 400 500 T mAb P mAb T/P REGULGENT (N-term) P/T REGULGENT (N-term) T/P REGULGENT (C-term) P/T REGULGENT (C-term) Titer (mg/L) T: TRAIL-R2 P: PSMA T/P REGULGENT (N-term) P/T REGULGENT (N-term) T/P REGULGENT (C-term) P/T REGULGENT (C-term) Transient expression, ExpiCHO-S cells (Day 8) 0 200 400 600 800 1000 1200 1400 1600 1800 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Titer (mg/L) Days P mAb T/P REGULGENT(N-term) Stable expression using CHO cells Kyowa Kirin R&D Briefing September 26, 2024: Presenter Alters Materials REGULGENTTM Productivity
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© Kyowa Kirin Co., Ltd.11 Cancer Antigen A /Target Antigen B Expression cell KK2260 Target antigen B positive cell Cancer Antigen A positive cell KK2269 target cells immune cell Only when binding to cancer antigens Blocks cellular iron uptake Patient-derived tumors in mice regress Only when binding to cancer antigens Activates anti-tumor immune cells Anti-tumor immunity makes implanted tumors regress target cell Broadly deployable technology, now in clinical trials Leveraging REGULGENTTM in multiple layers Efficacy Toxicity Efficacy Toxicity
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© Kyowa Kirin Co., Ltd.12 Our drug discovery approach, via REGULGENTTM *Generated AI-generated images
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© Kyowa Kirin Co., Ltd.13 APPENDIX
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© Kyowa Kirin Co., Ltd.14 PSMA antigen immunity Acquisition of PSMA antibodies with the same light chain as E11 using phage display REGULGENTTM phage Human Antibody- Producing Animals Screened a library fixed to the E11 light chain Obtained antibodies sharing a fully human light chain TRAIL-R2 antibody E11 TRAIL-R2 PSMA PSMA PSMA TRAIL-R2 TRAIL-R2 Common light chains Acquisition of light chain common antibody