STI-001 Program

Executive Summary

This document presents a summary of the key background data and development plans for Sorrento Therapeutics’ (STI’s) lead mAb development program (STI-001). In this program, a fully human antibody (IgG), derived from STI’s proprietary human mAb library and targeting STI’s proprietary target AIPs, is being developed for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) and other bacterial infection indications.

This document provides a broad overview of the therapeutic target, the therapeutic mAb development plan and the key in vitro and in vivo efficacy data plans for the program. It provides a description of the toxicology considerations, including the planned studies for results of exploratory toxicology before outlining the current plans for manufacture and clinical development of the molecule. The table below provides a headline summary of the program.
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PROGRAM OVERVIEW

Using technology pioneered at The Scripps Research Institute (TSRI) and licensed exclusively to Sorrento Therapeutics, Inc. (STI), unique approaches to controlling S. aureus infections, including those resistant to antibiotics, are in development. The Quorum Quenching (QQ) approach is unique in two significant ways. First, rather than attempting to directly eliminate bacteria associated with infection, the QQ approach modulates the global virulence of the invading pathogens, thus, allowing the bacteria to be cleared by the host’s immune system. Importantly, it is known that quorum sensing-deficient S. aureus strains are not able to efficiently establish infection, validating our approach. Second, the AIPs, the targets of our approach, are mutationally constrained by three key processes, making them preferred targets for intervention. Notably, the AIPs must interact with a bacterial processing enzyme and transporter plus a bacterial receptor in order to cause virulence. Although required for virulence, the AIPs are not essential for bacterial viability and growth per se, reducing the selective pressure for the generation of resistance.

Proof-of-concept experiments in mouse models conducted by our colleagues at TSRI (1) provide convincing data that monoclonal antibodies are effective in combating abscess formation in a skin and soft tissue infection model (Figure 1) and in preventing mortality due to S. aureus infection (Figure 2) .

Figure 1. Anti-AIP mAb Prevents S. aureus Dermal Injury.

SKH1 euthymic hairless mice received 200 L intradermal flank injections of S. aureus (1x108 bacteria) and Cytodex beads, PBS, or mAb AP4-24H11. After injections were made the mice were monitored at least three times per day over a period of 7 days. (A) S. aureus + PBS; (B) S. aureus + AP4-24H11 (0.06 mg); (C) S. aureus + AP4-24H11 (0.6 mg); (D) Cytodex + AP4-24H11 (0.6 mg).

Figure 2. Mice are Protected from Lethal S. aureus Challenge by Pretreatment with an anti-AIP4 mAb. Protection of mice from lethal S. aureus challenge by mAb AP4-24H11. Mice were pre-treated with AP4-24H11 or control IgG followed 2 h later by S. aureus injection (3x108 i.p.). The numbers in parenthesis show survivors per group. p = 0.001.

STI’s own patented technology, used to create human single chain variable fragment antibody libraries, is a perfect fit with the AIP targets. Fully human antibodies against S. aureus AIPs will be identified and developed into products to treat patients scheduled for surgery. The need for such a product is great. A 2009 study from Duke University Medical Center looking at MRSA infections associated with surgery compared to uninfected controls found a 35-fold increased risk of hospital readmission, a 7-fold increased risk of death, and more than $60,000 of additional charges per patient.

Preliminary studies conducted by our colleagues at TSRI also show great promise for conjugated AIPs as vaccines. In these studies 4 of 6 mice vaccinated with an AIP conjugate survived an S. aureus challenge despite having low titers of antibody; in contrast, only 3 of 12 control mice survived. Higher antibody titers are expected to offer even better survival rates.

Based on direct medical costs of $27,083 to $34,900 per patient (includes non-surgical infections) and CDC estimates of 120,000 patients hospitalized with MRSA in 2000, annual costs to treat hospitalized patients would be between $3.2 billion and $4.2 billion for the U.S. alone.

There is also a substantial market for agricultural use where S. aureus-caused inflammation of the mammary gland (mastitis) in dairy cows results in significant economic losses due to reduced milk production, degraded milk quality, early culling of cows, drug costs, veterinary expenses, and increased labor costs for the farmer. Fifteen years ago, the total economic losses due to mastitis were estimated to be about $2 billion annually for the USA alone(2-4).

1. Park, J., Jagasia, R., Kaufmann, G.F., Mathison, J.C., Ruiz, D.I., Moss, J.A., Meijler, M.M., Ulevitch, R.J. and Janda, K.D. Chem. & Biol. 2007, 14, 1119-1127.
2. Philpot, W. N. Veterinary Clinics of North America-Large Animal Practice 1984, 6, 233-245.
3. Degraves, F. J.; Fetrow, J. Veterinary Clinics of North America-Food Animal Practice 1993, 9, 421-434.
4. Allore, H. G.; Erb, H. N. Journal of Dairy Science 1998, 81, 2280-2292.

Contact Information

Martina Molsbergen
VP Business Development
Sorrento Therapeutics, Inc.
6042 Cornerstone Court West, Suite B
San Diego, CA 92121
Tel: 610-291-2726

Email: mmolsbergen@sorrentotherapeutics.com

http://www.sorrentotherapeutics.com/