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 SIWA 318

We have developed a family of monoclonal antibodies that have the same specificity based on a binding, complementarity determining region (“CDR”) sequence homology. Our lead product is a humanized monoclonal antibody (our “mAb” or “SIWA 318H”). It targets a SIWA-identified, naturally-occurring cell surface marker (our “SIWA Marker”) on both cancer cells and senescent cells (“SCs”), which cells are thereby destroyed and removed through normal processes. Our family of antibodies includes SIWA 318M, a murine homolog that we used in our early in vitro and in vivo studies.

 

DATA

SIWA has conducted several in vivo preclinical studies. which have shown that using SIWA 318 over a short period of time has been able to statistically significantly:

  • Reduce senescent cells as measured by p16INK4a
  • Increase muscle mass in a naturally aged mouse model
  • Inhibit metastatic lung foci in a 4T1 breast cancer model

Across these studies, no adverse effects from SIWA 318 were recorded.

 

Pilot study to test SIWA318H in a humanized mouse xenograft model for pancreatic cancer

Background:

SIWA318H is a novel monoclonal antibody that selectively targets a biomarker (an advanced glycation end product) found on the surface of cells exhibiting a combination of: (a) an abnormally high level of aerobic glycolysis, a process known to be associated with initiation and progression of cancer as well as metastasis; and (b) oxidative stress. Cells with this biomarker are often dysfunctional and associated with aging, cancer, and infectious diseases.

Methods:

As part of the clinical development of SIWA318H, we conducted a pilot study to evaluate dosing and scheduling of SIWA318H in a humanized xenograft model for pancreatic cancer. This pilot study was performed in preparation for a larger proof of concept study to determine efficacy of SIWA318H for treating pancreatic cancer. 
 
Previously, we established that SIWA318H binds in vitro to pancreatic cancer cells (PSN1 and PANC-1) and cancer associated fibroblasts (CAF08)
 
In this pilot study humanized CD34+ NSG mice were injected subcutaneously with PSN1 pancreatic cancer tumor cells. Ten days later, mice were enrolled in two groups (n=3 per group): 1) IgG1 isotype control and 2) SIWA318H. Mice were treated a total of 6 times twice a week. Tumor growth was evaluated by measuring tumor size twice weekly. 

Results:

The pancreatic tumor cell line PSN1 generated consistently measurable tumors in all CD34+ NSG mice injected. These tumors were easy to measure and were proven to be an adequate tumor model to evaluate biological effect of SIWA318H. Ten days after tumor implantation mice were treated with either isotype control or SIWA318H. Results show that tumors in mice treated with SIWA318H grew significantly slower than those in mice treated with isotype control antibody (p<0.001) (Figure 1).

Graph showing Tumor Volumes vs Time
Figure 1. Results of the pilot study for the treatment of pancreatic cancer in humanized mice.

Conclusions:

Results from the pilot study demonstrated that this tumor model is an adequate system to evaluate efficacy of SIWA318H to treat pancreatic cancer. In addition, the treatment dose and schedule showed a statistically significant tumor growth reduction when compared isotype control and SIWA318H treatment groups. 
We recently completed our larger efficacy/proof of concept study which had  results consistent with our Pilot Study results.  Additional data will be forthcoming pending publication.

 

Muscle Wasting Pre-Clinical Data

A study using a murine version of SIWA 318 in naturally-aged CD-1 mice achieved a statistically significant reduction in senescent cells, as measured by a reduction in p16INK4a. As expected, the reduction in senescent cells was coupled with a statistically significant increase in muscle mass, as measured in the gastrocnemius muscle, back to a level comparable to young mice controls. Study results were achieved with 3 weeks of twice daily injection of SIWA 318. Treated mice showed no adverse effects of treatment and no regression was observed in the post-treatment, 9-week treatment free period. The charts below show some of these results.

SIWA-Chart-One
Siwa-Chart-Two
 GREEN designates old mice at 2.5µg per gram
PURPLE designates old mice at 5µg per gram
BLUE designates young mice controls
RED designates old mice controls

 

Cancer Metastasis Results

 

A preclinical study showed that removal of senescent cells using a murine form of SIWA 318 significantly inhibited tumor metastasis. Importantly, there were no observable adverse effects from the treatment and no increase in tumor growth over the control group.

The study was done in a BALBc 4T1 metastatic breast cancer mouse model. Mice were grouped to receive 5 ug/g, 10 ug/g, or saline injections two times daily for three weeks. A fourth group received no treatment. When the study ended at 23 days, the 10ug/g group showed 30% (p < 0.001) fewer metastatic lung foci compared to the control group.

Metastatic Foci

Some Images of 318H Binding Results

PANC-1 Pancreatic Cancer cells
PANC-1 Pancreatic Cancer cells
Glioblastoma Cells
Glioblastoma Cells
Patient Derived Pancreatic Cancer cells
Patient derived pancreatic cancer (712)
Human Alzheimer Vascular Microglia
Human Alzheimer’s Vascular Microglia
Human Osteoarthritic Chondrocytes
Human Osteoarthritic Chondrocytes
PSN-1 Pancreatic Cancer
PSN-1 Pancreatic cancer

Other Products

Other Products. We are working on other products inherent in, or incorporating all or a portion of, SIWA 318H, including the following: Toxin-conjugated single domain molecules. We have patent coverage for attaching all or the binding portion of SIWA 318H to a toxin. A toxin conjugated fragment of our antibody may be particularly useful for treating sites with barriers to large molecules (such as the brain, eyes, solid tumors and joints). Vaccines. Using our SIWA Marker (the cell surface antigen that binds to SIWA 318), we have constructed a preliminary immunogen vaccine for use in immunizing against SCs. This would be particularly useful in products for veterinary applications (e.g. in beef and dairy cattle, service animals, pets, and horses). Diagnostic Testing. We are developing a diagnostic test to detect SCs e.g. in the blood based on binding to a labeled version of our monoclonal antibody. This could, by way of example, alert patients of the need for SIWA 318H SC removal treatment. Separatory and/or Purification Equipment. Separatory and purification applications include removing SCs from banked blood and from stem cells for transplants to improve transplant quality for injection into patients. Similarly, SIWA 318H or a binding fragment thereof may be attached to a support (e.g. beads in a column) to attach to and remove SCs from any type of cells being implanted into a patient (e.g. chondrocytes or stem cells injected into joints to treat joint damage). We are developing a cell separator system for use, inter alia, in separating senescent stem cells from stem cell mixtures. For more information, or to discuss partnering with us, please contact: Lewis S. Gruber, CEO lsgruber@siwatherapeutics.com