Serina Therapeutics, Inc. · AMEX:SER
Serina Therapeutics — 4th mRNA-based Therapeutics Summit 2024
34 slides from Serina Therapeutics's conference presentation, Jul 29, 2024
Slide 1: Overcoming Anti-PEG Antibody Responses to Increase Potency & Decrease Adverse Side Effects of mRNA-LNP Formulations
ae Overcoming Anti-PEG Antibody Responses to Increase Potency & Decrease Adverse Side Effects of MRNA-LNP Formulations Randall Moreadith, MD, PhD, Chief Development Officer July 29, 2024 4th mRNA-based Therapeutics Summit - Boston, MA
Slide 2: POZ Platform
POZ Platform® Enabling Technology Small Molecules RNA ADCs New / improved Optimized targeting & Improved delivery of small molecule drugs reduced immunogenicity cancer-killing toxins Clinically validated
Slide 3: Forward Looking Statements
Forward Looking Statements This presentation contains forward-looking statements that are based on management's beliefs and assumptions and on information currently available to management. In some cases, you can identify forward-looking statements by the following words: “may,” “will,” “could,” “wo
Slide 4: Today's Messaging
Today's Messaging: * — Anaphylaxis occurs at an unusually high incidence rate in patients receiving the approved mRNA vaccines; it is not classically characterized IgE-mediated (mast cell degranulation) * The high titers of IgM & IgG that are boosted by the vaccines bind to LNPs, activate complement
Slide 5: Anatomy of LNPs
Anatomy of LNPs What if replacing the PEG-lipid with a POZ-lipid resulted in something truly extraordinary ? @=— lonizable lipid @@ Cholesterol QS mRNA @— Phospholipid SE PEGC-lipid @=— lonizable lipid @@ Cholesterol RS mRNA @— Phospholipid Se POZ-lipid
Slide 6: Balancing immunogenicity and reactogenicity
Balancing immunogenicity and reactogenicity Review www.nature.com/emm BW) Check for updates REVIEW ARTICLE OPEN Knife’s edge: Balancing immunogenicity and reactogenicity in mRNA vaccines Jisun Lee"®, Matthew C. Woodruff?°, Eui Ho Kim*”* and Jae-Hwan Nam@"°" © The Author(s) 2023
Slide 7: Balancing immunogenicity and reactogenicity
Balancing immunogenicity and reactogenicity List of adverse events reported with the mRNA vaccines Psychiatric disorders “Anxie! \Neuroieptic malignant syndrome Eye/Ear diaorders Tinnitus/Vertigo Meniere's disease Inner ear disease Hearing loss Uveitis/Blurred vision Bell's palsy Optic neuropathy Re
Slide 8: In First Wave of Vaccinations Anaphylaxis Was Noted
In First Wave of Vaccinations Anaphylaxis Was Noted Occurred primarily in women (~ 90%) COVID-19 Pfizer’s vaccine raises allergy concerns Polymer in mRNA‘s “packaging” may cause rare anaphylactic reactions By Jop de Vrieze COVID-19 CORRESPONDENCE Anaphylaxis to the first COVID-19 vaccine: is polyeth
Slide 9: In A Consecutive Cohort Study in Japan of Pfizer/BioNTech Vaccine
In A Consecutive Cohort Study in Japan of Pfizer/BioNTech Vaccine Occurred primarily in women (~ 90%) Letter to the Editor The incidence rate of anaphylaxis Sex differences in the incidence of anaphylaxis was 1:13,882 to LNP-mRNA COVID-19 vaccines On February 17, 2021, Japan started vaccinating heal
Slide 10: Living patients in Stanford Medicine Network
4212410 Living patients in Stanford Medicine Network as of January 26, 2021 J 38895 Vaccines administered by Stanford Medicine? from December 18, 2020, to January 26, 2021 31635 BNT162B2 mRNA vaccines 7260 mRNA-1273 vaccines J 148 Patients received T78.2XXA, T80.52XA, T78.2XXD, or E949.9 codes? v v
Slide 11: Is PEG the culprit? Yes.
Is PEG the culprit ? Yes. MAIN OUTCOMES AND MEASURES Allergic reactions were graded using standard definitions, including Brighton criteria. Skin prick testing was conducted to polyethylene glycol (PEG) and polysorbate 80 (P80). Histamine (1 mg/mL) and filtered saline (negative control) were used fo
Slide 12: Basophil Activation Testing (BAT) Assay on Example Participant
Figure 2. Basophil Activation Testing (BAT) Assay on Example Participant Using Vaccine, Anti-Immunoglobulin E (IgE), and Saline A] vaccine [B] Anti-IgE [C] Saline 200000- 2000004 200000+ 150000- 1500004 1500004 = y 100000- 100000- = 100000. 50000- 50000~+ 50000 . . cl nar CO Ot peg opr rp aera o- ap
Slide 13: Does vaccination induce high titers of anti-PEG antibodies?
Does vaccination induce high titers of anti-PEG antibodies ? Review of recent literature Anti-PEG Antibodies Boosted in Humans by SARS-CoV-2 Lipid Nanoparticle mRNA Vaccine Yi Ju,* Wen Shi Lee, Emily H. Pilkington, Hannah G. Kelly, Shiyao Li, Kevin J. Selva, Kathleen M. Wragg, Kanta Subbarao, Thi H.
Slide 14: Does vaccination induce high titers of anti-PEG antibodies?
Does vaccination induce high titers of anti-PEG antibodies ? Is this a proximate cause of reactogenicity ? “\ COVID-19 lipid es nanoparticle mRNA vaccine » Influences Anti-PEG antibodies PEGylated nanoparticle- boosted inhuman plasma immune cell association in human blood Heserina
Slide 15: Does vaccination induce high titers of anti-PEG antibodies? Absolutely.
Does vaccination induce high titers of anti-PEG antibodies ? Absolutely. Anti-PEG IgG 45 Anti-PEG IgG Endpoint Dilution (1/10*) A BNT162b2 Vaccination Anti-PEG IgM Endpoint Dilution (1/10*) Anti-PEG IgM B_ mRNA-1273 Vaccination Anti-PEG IgG S <0,0001 S = 45 -— = = © 5 § 3 3 a 34 a =z = 8 8 ne] nol i
Slide 16: Does vaccination lead to higher rates of reactogenicity?
Does vaccination lead to higher rates of reactogenicity ? Local (injection site) vs systemic (overall symptoms) as a function of Log,, titer IgG Local Reactogenicity Post-Boost Local 40 Systemic p=0.3271| . . p=0.0025 r=0.1255 is 3 r=0,3746 5 33 |. e e e 3 8 6{ © wee e ga oe r) ome 00 © gz 45 @ee e
Slide 17: Does vaccination lead to binding of nanoparticles to immune cells?
Does vaccination lead to binding of nanoparticles to immune cells ? Given high titers of IgG and IgM — does this result in binding of PEG-containing nanoparticles by immune cells ? Scheme 1. Schematic Illustration of Human Blood Assay to Assess the Impact of Plasma on PEGylated Nanoparticle Associat
Slide 18: Does vaccination lead to binding of nanoparticles to immune cells?
Does vaccination lead to binding of nanoparticles to immune cells ? Given high titers of IgG and IgM — does this result in binding of PEG-containing nanoparticles by immune cells ? B Change in Anti-PEG Antibody after Vaccination vs. Change in LNP-Immune Cell Association Anti-PEG IgG vs. Anti-PEG IgG
Slide 19: Does vaccination lead to complement activation?
Does vaccination lead to complement activation ? Moderna vaccination resulted in binding of C1q by anti-PEG IgG and IgM A Anti-PEG Antibody-Mediated C1q Binding) 3-5 mmm Pre-Vax == Post-Boost E 8 2 2 The higher titers of anti-PEG IgG z 3 and IgM induced by Moderna . L vaccination (post boost) led to
Slide 20: Does vaccination lead to complement activation?
Does vaccination lead to complement activation ? It is clear that the anti-PEG antibodies bind complement ... but do they compromise the LNP (study 2022) ? Anti-PEG antibodies compromise the integrity of PEGylated lipid-based nanoparticles via complement Mariona Estapé Senti®”»®', Caroline A. de Jon
Slide 21: Substitution of PEG-dmg with PEOZ-dmg
Substitution of PEG-dmg with PEOZ-dmg Studies performed in collaboration with the James DahIman Laboratory (2021-2023) Substituting Poly(ethylene glycol) Lipids with Poly(2-ethyl-2-oxazoline) Lipids Improves Lipid Nanoparticle Repeat Dosing Alejandro J. Da Silva Sanchez, David Loughrey, Elisa Schrad
Slide 22: The Accelerated Blood Clearance (ABC) Phenomenon
The Accelerated Blood Clearance (ABC) Phenomenon Studies performed in collaboration with the Dahlman Laboratory (2021-2023) Biophysical properties (size, polydispersity, EE) are similar — but not identical A B c Moderna LNP Composition ta 15 £150 8 100 DMG-PEG 50 EOZ 2 DSPC - a ° 0 D E F x 0.3 125 3
Slide 23: POZ-lipid LNPs Have Unique Properties — IV Infusion
POZ-lipid LNPs Have Unique Properties — IV Infusion LNPs which incorporate PEOZ-dmg selectively express the payload in macrophage (M) and dendritic (D) cells A Moderna LNP Composition MC3LNP. Composition B DMG-PEG PEOZ DSPC n <. Qc Cell Types Endothelial (E): CD31+ Dendritic (D): CD45+, CD11¢+ Macro
Slide 24: The Accelerated Blood Clearance (ABC) Phenomenon
The Accelerated Blood Clearance (ABC) Phenomenon Studies performed in collaboration with the Dahlman Laboratory (2021-2023) Weekly dosing of PEG-dmg vs 2K PEOZ-dmg with a luciferase payload A Total RNA Dose: B 0.25 mg/kg mouse PBS ‘ Sey ~ PEG, Group B “ts Ree “ts Ree Group B Rap, T “Ray - us ~ ~ ~ P
Slide 25: Evaluation of Pfizer/BioNTech LNP in rat - PEG-dma
Evaluation of Pfizer/BioNTech LNP in rat - PEG-dma Rat immunogenicity study (The LNPs in this study employed ALC-0315 and ALC-0159 (Acuitas) at mol% for the published vaccine) Nn pj vaccl nes www.nature.com/npjvaccines ARTICLE OPEN |® Check for updates: Polyethylene glycol (PEG)-associated immune re
Slide 26: Does vaccination with clinically relevant LNPs lead to anti-PEG Abs
Does vaccination with clinically relevant LNPs lead to anti-PEG Abs Rat immunogenicity study (Pfizer/BioNTech vaccine formulation) Clinically relevant dosing modeled after First injection Second injection C-19 vaccines a x 2 © Control (PBS) \ © L-LNP ( 0.009 mg phospholipids/kg LNP) X “ X ‘ © M-LNP
Slide 27: Anti-PEG antibody induction in rat
Anti-PEG antibody induction in rat Boosted anti-PEG antibodies - IgM and IgG are both boosted (similar to human data) D 5 35 = Control = Control o = L-LNP = Zz = M-LNP 9) iS = H-LNP 4 1) ° A is) ee = hs ¥ & g As a a r=) : & = 3 2 p= i < a me i Oa | T pe T ——j—— © 337 14 21 242628 35 42 49 8 357 14 2
Slide 28: Does vaccination with PEOZ-dma vs PEG-dma lead to different anti-PEG response
Does vaccination with PEOZ-dma vs PEG-dma lead to different anti-PEG response Serina study design to evaluate PEOZ-dma and PEG-dma First Injection Second Injection The High Dose — 2.0 mg " : phospholipid / kg body weight e Ss The Mid Dose — 0.2 mg LY F X - phospholipid / kg body weight Q. . Or, +— +
Slide 29: Phospholipid content, Particle size, Polydispersity, Zeta Potential & Encapsulation efficiency
Phospholipid content, Particle size, Polydispersity, Zeta Potential & Encapsulation efficiency Standard Curve pGFP PEG PEOZ PEG PEOZ w/o TX w/ TX 2 a . 09 + 06 03 = H H 3 Hi 3 Concentration Phospholipid Standards After Buffer Exchange in Tris-HCl, pH 7.1 Signal Sample Name Z-Average (nm) Polydispers
Slide 30: Anti-IgM antibodies to PEG-dma vs PEOZ-dma
Anti-lgM antibodies to PEG-dma vs PEOZ-dma Serina LNP Laboratory z 19000 -® IgMPEG20 > 6000 a -& IgM PEGO2 S =e IgM PEOZ 2.0 _ = IgM PEOZ 0.2 2000 = > f ro} f o. P=] 0 & < 0 10 20 30 Days 0 - 28 Anti-lgM antibodies are readily detected, and boosted, at the High Dose and Mid Dose when LNPs employing
Slide 31: Anti-IgG antibodies to PEG-dma vs PEOZ-dma
Anti-lgG antibodies to PEG-dma vs PEOZ-dma Serina LNP Laboratorv z 1200 © IgGPEG20 > 1000 “& IgG PEG02 oO -t- IgG PEOZ2.0 Q 800 po =—% IgG PEOZ 0.2 fi 600 = 400 re} f 2 200 = 0 < T 7 T T T T T 0 10 20 30 Days 0 - 28 Anti-lgG antibodies are readily detected at both the High Dose and Mid Dose when LNP
Slide 32: Today's Messages
Today's Messages: * Anaphylaxis to the vaccines appears to be due to basophil degranulation, likely the result of high titer IgG (possibly IgM) to the PEG in the formulation * Now recognized as an uncommon mechanism of anaphylaxis, first described clinically ~ 15 years ago * — The high titers of IgM
Slide 33: Thank You
Thank You
Slide 34: Balancing immunogenicity and reactogenicity
Balancing immunogenicity and reactogenicity Serina’s technology is poised to advance v2.0 & v3.0 vaccines mRNA-LNP Serina’s PEOZ-LNP Selectively targets this population of immune cells Memory B cell Long-lived plasma cell a? — Cell death @ T cell o Virus infected cell t¥ serina 34
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