Research

Cell adhesion molecules, e.g., integrin, intercellular adhesion molecule, selectin, mediate cell-cell and cell-matrix interaction, and are important therapeutic targets in autoimmune-related diseases and cancer. Integrins are a family of heterodimers of alpha and beta subunits, and each of subunits consists of multiple modular domains, among which one or two domains serve as ligand-binding sites. Integrins exhibit sophisticated allosteric conformational change of bent to extended conformation induced either by signals from inside (inside-out signaling) or by ligand binding to integrins (outside-in signaling)(Figure 1). Previously we have studied experimentally and computationally an allosteric activation mechanism of ligand binding domain of some members of integrins, known as Inserted or I domain. Impressively, using various protein engineering tools, we haveengineered an I domain with an increase of 200,000-fold in the affinity to Intercellular adhesion molecule-1 (ICAM-1). When the high affinity I domain mutant was tested for a potential therapeutic use in blocking the migration of leukocyte through endothelium whose aberrant activation is associated with autoimmune-related diseases, it was found to be as effective as anti-LFA-1 antibody or Raptiva that was approved for treating psoriasis.

ICAM-1 is a ligand for some integrins and subverted as a receptor for human rhinovirus, which is the major causative agent of the common colds. ICAM-1 was shown to be effective in preventing rhinovirus infection in clinical studies, but the high cost of producing ICAM-1 from mammalian system prevented a further development. We are developing a single domain of ICAM-1 (D1) to be functional for virus binding and amenable for large-scale production from bacteria. High resolution structure of rhinovirus in complex with D1 may also facilitate developing small molecule drugs that inhibit rhinovirus infection.

Most antibodies for passive immunotherapy are generated using hybridoma technology involving immunization of animals with antigens, where the process is labor-intensive, time-consuming, and lacks flexibility to respond to the ability of infectious agents and toxins to acquire antibody-escaping mutations. We are developing a strategy that will lend flexibility in responding to new, diverse, and evolving organisms, and thereby enhance our ability to respond quickly to the urgent need for immunotherapy against a growing number of emerging pathogens. Our novel platform is demonstrated to be highly efficient in engineering antibodies for therapeutic values such as conformation-specificity, cross-reactivity, and high affinity.

Tumor Targeting Nanoparticles: Two major hurdles in cancer therapy are early detection of tumor in the body and efficient delivery of drugs to the tumor cell target. We are developing magnetic resonance contrast agent based on nanoparticles that are coated with tumor targeting biomolecules that are designed to recognize unique and over-expressed markers on tumor cell surface and environment. In parallel, we are investigating the use of surface-modified liposomes that encapsulate magnetic nanoparticles and cancer drugs to provide a dual functionality as tumor diagnostics and therapeutics.

Adeno-associated virus (AAV) mediated gene delivery targeting brain and connective tissue. AAV is a non-pathogenic virus, and yields long-term gene transfer and minimal toxicity as a gene delivery system. We are interested in modifying viral capsid protein to create new tropism for the virus for efficient gene delivery into different tissues and for direct transport through the BBB into the brain.