1. Transforming Medicine: Monoclonal antibody for senescent cell clearance as a treatment for cancer and aging-associated and degenerative diseases
SIWA THERAPEUTICS, INC.
400 E. Randolph Street
Suite 700
Chicago, IL 60601

2. SIWA THERAPEUTICS, INC. AND SLOWING OF AGING
We founded SIWA to develop therapies, including our SIWA 318 monoclonal antibody, for slowing or reversing the aging process by removing senescent cells. These cells interfere with normal functions of other cells; thus, removing them potentially results in healthspan and lifespan benefits. We have shown that SIWA 318 targets and destroys senescent cells in vivo and thus is designed to positively impact healthspan as well as lifespan. However, as the FDA currently does not recognize aging as a disease indication, we have focused instead on aging-related diseases in which senescent cells are implicated. 2

3. SIWA Therapeutics is: A Pre-Clinical Stage Company with:
A first-in-class humanized monoclonal antibody, SIWA 318H, that targets and destroys senescent cells
The SIWA 318M murine homolog has demonstrated activity in mouse disease models with no negative side effects
A significant patent portfolio 3

4. Our SIWA mAb (SIWA 318H)
We have the complete sequence of SIWA 318H, which gives us the software for senescent cell clearance.
SIWA 318H is recombinately expressed and can thus be modified/updated as opportunities present themselves
SIWA 318H does not interfere with the senescence process itself
SIWA 318H can be configured as bispecific to target senescent cell clearance to a selected location and an identified species at that location

5. SIWA 318: Reduces Senescent Cells In Naturally Aged Mice
Statistically significant reduction in standard senescent cell biomarker
p16Ink4a mRNA expression levels:
2.55x in untreated aged mice (≅ 91 weeks) vs. untreated young mice at study initiation
Remained 3.03x higher in the untreated vs. treated aged mice
Reduced statistically significantly in aged mice following injection of murine SIWA 318
Young mice controls Old mice controls
Old mice at 2.5µg per gram* Old mice at 5µg per gram*
*Dose administered BID once a week for 3 weeks 5

6. Other Products For Revenue Generation
Toxin conjugated single domain molecules A toxin conjugated fragment of SIWA 318 may be particularly useful for treating privileged sites with barriers to large molecules (such as the brain and joints).
Separatory Equipment SIWA 318 or a binding fragment thereof may be used to remove senescent cells from banked blood or to remove senescent cells from any type of cells being implanted into a patient (e.g. chondrocytes in joints to treat joint damage).
Database
We are developing a senescent cell prevalence database regarding mAb binding to normal and diseased tissue. 6

7. Cardiovasc. (Foam cells)
Senescent Cells Promote Diseases Including Cancers Based on the Tissue in Which They Occur
Senescent Cells:
Lose function and ability to divide, do not reproduce, but spread by conversion
Have a high metabolic rate and synthesize and accumulate proteins leading to secretion of damaging inflammatory factors
May be stress induced: e.g. genetic dysfunction and chemotherapy
Brain (glial cells) Alzheimer's, Parkinson's
Damage/Stress
Physical Injury, chemicals genetic disorders, mutations, Infection, growth overstimulation
Muscle (stem cells) Duchenne & ALS
Cardiovasc. (Foam cells)
Atherosclerosis.
Cellular Senescence
Joints (chondrocytes, T- cells, Synoviocytes)
Osteoarthritis, Rheumatoid arthritis, & JRA 7

8. SOME IN VITRO RESULTS
Neuro-degenerative diseases. Researchers at the ASU-Banner Neurodegenerative Disease Research Center demonstrated in vitro for us that SIWA 318M bound to disease-associated human cells (e.g., Astrocytes and glial cells) from Alzheimer’s disease, Parkinson’s disease and ALS.
Osteoarthritis. We demonstrated in vitro that (a) human osteoarthritic chondrocytes (implicated in OA and rheumatoid arthritis) are senescent; (b) our humanized mAb bound to osteoarthritic chondrocytes (cartilage-forming cells in the joints) in sections of human joint tissue from patients undergoing joint replacement and (c) our mAb binds to senescent chondrocytes but did not bind to normal chondrocytes.

9. Photomicrograph of SIWA 318H our Humanized Antibody Binding to Chondrocytes in Human Osteoarthritic Cartilage

10. The Murine homolog of SIWA 318H binds to Vascular Glial Cells
Human Alzheimer’s Vascular Microglia 100x

11. Association with Amyloid Precursor Protein: SIWA Anti-AGE mAb (RED) Amyloid Precursor Protein (GREEN) Hippocampus AD
SIWA Anti-AGE mAb (Red)
Amyloid Precursor Protein (Green)
Hippocampus AD

12. Several types of cells have been shown to be associated with (a) upregulation of amyloid precursor protein (“APP”) and (b) senescent cells and the SIWA AGE biomarker. For example, APP upregulation in glial cells in Alzheimer’s Disease, and cancer cells including glioma cells, glioblastoma cells, senescent cells, prostate cancer cells, and pancreatic cancer cells.
APP in cancer is associated with proliferation, invasiveness and metastasis.

13. APPLYING SIWA 318 TO CANCER
Cancer. In cancer, we demonstrated in vitro that SIWA 318M binds cells of a human cancer cell line isolated from a histiocytic lymphoma (one of the most common cancers in the US). We followed the in vitro cancer work with an in vivo study in mice wherein we showed a statistically significant (30%) reduction in metastasis with our mAb treatment (see chart below). Our blood brain barrier work with a group in Berlin that suggests that SIWA 18M crosses the blood brain barrier, which is relevant to cancers that originate in and/or metastasize to, the brain. We recently entered into a material transfer agreement with university researchers who will study the impact of SIWA 318 on pancreatic cancer. We also are finalizing an agreement for a cancer study to be done with a university group in France.

14. SIWA vs CANCER 
Cancer incidence rises exponentially in the final decades of life – persons over 65 account for 70% of cancer deaths
The murine homolog of SIWA 318H binds to:
human histiocytic lymphoma cells;
human vascular glial cells in brain sections from Alzheimer’s Disease patients whereat it colocalized with p16INK4a
Vascular glial cells accumulate amyloid precursors and participate in gliomas (a type of brain cancer which includes glioblastomas in older individuals and diffuse intrinsic pontine gliomas in children). Neither has a good prognosis.  
Gene expression in Alzheimer’s disease and glioblastomas are directly correlated. (Sanchez Yelle 2017)

15. Pancreatic carcinoma associated fibroblasts exhibiting a p16INK4a senescence marker increase cancer cell invasiveness and metastasis (Navab 2016).
The murine homolog of SIWA 318H significantly reduced p16INK4a expressing cells in mice; it also significantly reduced metastasis in a mouse adenocarcinoma metastasis model.

16. SIWA 318M: Senescent Cell Clearing Inhibits Adenocarcinoma Tumor Metastasis
Key Findings: Statistically significant (30%) inhibition of metastatic lung foci in a mouse 4T1 metastatic adenocarcinoma model using 10 µg/gram (2x daily for 3 weeks)
Trending toward tumor decrease - no increase in tumor growth in treated animals over controls Body weights showed a trend toward increase in treated animals
Saline 5 µg/gram 10 µg/gram
2x daily administration for 3 weeks
Enumerated Foci
Metastatic Foci on Day 23
(p < 0.001) 16

17. SIWA 318: The Good News: Muscle Regeneration Occurs in Naturally Aged Mice with senescent cell reduction after Muscle Wasting
Statistically significant increase of gastrocnemius muscle weight vs. age-matched controls Antibody-dependent effect instigated at 5 µg/gram in naturally aged mice (≅ 91 weeks) No adverse effects or regression in post-treatment, 9-week treatment free period
Young mice controls Old mice controls
Old mice at 2.5µg per gram* Old mice at 5µg per gram*
*Dose administered BID once a week for 3 wks.
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