S.M.A.R.T. Immunoliposome Technology (Bibliography)

HERMES efforts resulted in the development of a new generation of molecularly targeted nanocarriers. This includes HERMES’ proprietary S.M.A.R.T. (stabilized, modularly-assembled, receptor-targeted) Immunoliposome technology, utilizing antibody-guided liposomes (immunoliposomes) directed against cell surface receptors in cancer or other target cells. HERMES’ S.M.A.R.T. Immunoliposomes represent a powerful platform technology. For example, immunoliposomes directed against the HER2/ErbB2/neu (anti-HER2 immunoliposomes) or EGFR (anti-EGFR immunoliposomes) oncogene were shown to efficiently bind to and become internalized by cancer cells in vitro and in vivo, resulting in targeted intracellular drug delivery.

Recent studies have also demonstrated a wide range of immunoliposome constructs against a range of breast cancer and prostate-cancer specific cell surface antigens.  For the HER2-immunoliposomes, the result of this cancer cell-specific targeting is a striking enhancement of therapeutic efficacy compared with the best non-targeted liposomes on the market, and is superior as well to treatment with anti-HER2 monoclonal antibody alone or in combination with chemotherapy. Anti-HER2 immunoliposomes containing HERMES’ proprietary antibody fragment F5 and the chemotherapy drug doxorubicin are in joint development toward clinical trials under the sponsorship of the National Cancer Institute (NCI) and ALZA Corp/Johnson&Johnson.

Exploiting the wide versatility inherent in S.M.A.R.T. Immunoliposome technology, HERMES is developing a variety of new immunoliposomal therapeutics. These are being generated using a combinatorial approach with HERMES’ liposomal drug repertoire and human antibody libraries.

HERMES is developing novel liposome- and nanoparticle-based drugs, in which potent compounds, obtained from a variety of sources, are encapsulated in new generation liposomes, lipid-based carriers, or nanoparticles. These drugs include both validated chemotherapeutics as well as novel chemical entities. In 2000, HERMES received an expanded SBIR for development of novel liposomal- and immunoliposomal drugs using potent anticancer compounds from the NCI Developmental Therapeutics Program (DTP).

Hermes Phage scFv Antibody Libraries and Antibody Selection Technologies (Bibliography)

HERMES' liposome technologies are closely integrated with its monoclonal antibody technologies. HERMES has developed phage antibody libraries tailored for rapid identification of new antibody fragments for use in S.M.A.R.T. Immunoliposomes.   Through its merger with CaRa in 2004, HERMES obtained exclusive rights to the high diversity phage display library of Bradbury and colleagues.   HERMES is developing immunoliposomes directed against additional targets, e.g., immunoliposomes directed against other oncogenic receptor-tyrosine kinases, prostate-specific epitopes, and immunoliposomes directed against endothelial receptors involved in angiogenesis, as well as against novel cell surface epitopes overexpressed in common cancers.

Phage antibody libraries have become an important technology in the selection of human antibodies against targets of therapeutic interest, with one approved, and many other human antibodies in clinical trials, derived using this technology. Most phage antibody libraries are created by cloning, and consequently have diversities no greater than ten billion clones. The Hermes Library uses site specific recombination to create libraries so large that diversity is limited only by the culture volume used to amplify the library. This library has been widely used to select antibodies against many different targets with affinities in the low nanomolar range routinely obtained.

Nanoliposomes - Lipotrap Stabilization Technology (Bibliography)

HERMES has developed proprietary liposome loading and intraliposomal stabilization technology (Lipotrap™) for stable encapsulation of a wide range of potent anticancer drugs in liposomes.  The fortuitous ease with which anthracyclines have been stably encapsulated in liposomes using conventional remote-loading strategies has been difficult to replicate with other classes of drugs, often resulting in premature leakage of the drug while in the circulation.  Premature drug escape from nanocarriers has been a serious impediment to liposomal drug development in the past. 

HERMES technology involves the formation of a highly stable complex of the drug with an intraliposomal trapping agent, resulting in liposomal and immunoliposomal formulations with drug-leak rates that approximate the rate of clearance of the liposomal carrier.  Therefore, lipotrap stabilization results in liposomes that are capable of delivering their therapeutic payload to its therapeutic target without losing the active agent prematurely in the blood.  The result has been a marked improvement in antitumor efficacy for a number of different potent anti-cancer agents; including vinorelbine, vincristine, topotecan, and irinotecan in a manner that results in a clear competitive advantage over other liposome formulation strategies.  Two of these “stabilized” nanoliposome formulations, nanoliposomal vinorelbine and nanoliposomal irinotecan, are currently being tested in various clinical trials around the world.

Convection Enhanced Delivery of Nanoliposomal Anticancer Therapeutics (Bibliography)

HERMES scientists have collaborated with UCSF investigators to deliver HERMES highly stable Nanoliposomal Camptothecin (Irinotecan or Topotecan) constructs directly into the brain using convection-enhanced delivery (CED) for the treatment of various brain neoplasms.  This therapy has resulted in extensive distribution and retention of the entrapped liposomal camptothecin in brain tumors, which can also be spatially controlled through visualization of similarly designed liposomes containing MRI contrast agents.  A Phase I/II trial using CED of Nanoliposomal Irinotecan in patients bearing malignant gliomas is currently being planned.

Genospheres™ – Nonviral Lipidic Nanocarriers for Nucleic Acid Delivery (Bibliography)

HERMES has adapted its immunotargeted lipidic delivery system for gene therapy. This novel non-viral gene vector technology, Genospheres™, is based on HERMES’ unique expertise in the areas of liposome formulation, membrane biophysics, and immunotargeting.  These highly stable lipidic nanocarriers are small, scalable, highly stable, long circulating, and show high transfection activity when targeted using a targeting ligand that promotes endocytosis.  Genospheres™ are suitable for delivery of nucleic acid therapeutics of a wide range of sizes and chemical modifications, including plasmid DNA, antisense oligonucleotides, and siRNA.

Remote-Sensing Liposomal Drug and Imaging Agents

HERMES scientists have developed a series of technologies for derivatizing liposomes or liposomal therapeutics for noninvasive detection of in vivo drug delivery.  These technologies include encapsulated MRI contrast agents for following the distribution of liposome in the brain following convection-enhanced delivery, stably encapsulated optical imaging agents, and insertable PEG-lipid chelates of radionuclides capable of remote-detection of liposome biodistribution and pharmacokinetics by SPECT.   These agents can be used to guide the delivery of liposomal agents, predict the effectiveness of drug delivery using liposomal therapeutics, or report on the on the course of treatment of a targeted liposomal therapeutic agent.

HERMES is also developing new drug carriers with unique biophysical characteristics. Examples include pH-sensitive liposomes for controlled intracellular release, stabilized nanoparticulate colloids for high efficiency drug formulation, and novel drug hydrosol formulations.