Physicians

DOCK-AND-LOCKTM

Background

Together with IBC Pharmaceuticals, Inc., we have developed a new platform technology, called the DOCK-AND-LOCKTM method, or DNLTM, which has the potential for making a considerable number of bioactive molecules of increasing complexity. DNLTM utilizes the natural interaction between two proteins, cyclic AMP-dependent protein kinase, or PKA, and A-kinase anchoring proteins, or AKAPs. The region that is involved in such interaction for PKA is called the dimerization and docking domain, or DDD, which always appears in pairs. Its binding partner in AKAPs is the anchoring domain, or AD. When mixed together, DDD and AD will bind with each other spontaneously to form a binary complex, a process termed docking. Once “docked,” certain amino acid residues incorporated into DDD and AD will react with each other to “lock” them into a stably-tethered structure. Since DDD always appears in pairs, any component that is linked to DDD will have two copies present in the final products. The outcome of DNLTM is the exclusive generation of a stable complex, in a quantitative manner that retains the full biological activities of its individual components. A description of the DNLTM platform technology was published in the September 15, 2007, Supplement issue of Clinical Cancer Research.

DNLTM judiciously combines conjugation chemistry and genetic engineering to enable the creation of novel human therapeutics, and the potential construction of improved recombinant products over those currently on the market. Diverse drugs, chemical polymers, proteins, peptides, and nucleic acids are among suitable components that can be linked to either DDD or AD. Since the invention of DNLTM, we have created multivalent, mono- or multi-specific antibodies; DNL-PEGylated cytokines; and cytokine-antibody conjugates. Results from in-vitro and in-vivo testing of these novel protein constructs have been reported in major scientific and medical conferences.

An immunocytokine, named 20-2b, comprising Veltuzumab and four copies of interferon-alpha (IFNα) was developed using DNLTM. 20-2b potently kills Non-Hodgkin Lymphoma (NHL) cells in vitro and exhibits remarkable in-vivo efficacy in human NHL xenograft animal models. This novel immunocytokine is being developed as a biologic therapeutic agent for NHL therapy with funding of a Phase II Small Business Innovation Research Grant from the National Institutes of Health.

Additional antibody-IFNα conjugates are in pre-clinical development for different indications. These include C2-2b-2b, which may be useful for the therapy of diverse hematopoietic malignancies, and several immunocytokines directed towards various solid tumors.

References
  1. Preclinical studies on targeted delivery of multiple IFN{alpha}2b to HLA-DR in diverse hematologic cancers. E.A. Rossi, D.L. Rossi, T.M. Cardillo, R. Stein, D.M. Goldenberg, C.H. Chang. Blood 118:1877-1884, 2011.

  2. A bispecific antibody-IFNalpha2b immunocytokine targeting CD20 and HLA-DR is highly toxic to human lymphoma and multiple myeloma cells. E.A. Rossi, D.L. Rossi, R. Stein, D.M. Goldenberg, C.H. Chang. Cancer Res 70:7600-7609, 2010.

  3. A new method to produce monoPEGylated dimeric cytokines shown with human interferon-alpha2b. C.H. Chang, E.A. Rossi, T.M. Cardillo, D.L. Nordstrom, W.J. McBride, D.M. Goldenberg. Bioconjug Chem 20:1899-1907, 2009.

  4. CD20-targeted tetrameric interferon-alpha, a novel and potent immunocytokine for the therapy of B-cell lymphomas. E.A. Rossi, D.M. Goldenberg, T.M. Cardillo, R. Stein, C.H. Chang. Blood 114:3864-3871, 2009.

  5. Hexavalent bispecific antibodies represent a new class of anticancer therapeutics: 1. E.A. Rossi, D.M. Goldenberg, T.M. Cardillo, R. Stein, C.H. Chang. Properties of anti-CD20/CD22 antibodies in lymphoma. Blood 113:6161-6171, 2009.

  6. Novel designs of multivalent anti-CD20 humanized antibodies as improved lymphoma therapeutics. E.A. Rossi, D.M. Goldenberg, T.M. Cardillo, R. Stein, Y. Wang, C.H. Chang. Cancer Res 68:8384-8392, 2008.

  7. Multifunctional antibodies by the Dock-and-Lock method for improved cancer imaging and therapy by pretargeting. D.M. Goldenberg, E.A. Rossi, R.M. Sharkey, W.J. McBride, C.H. Chang. J Nucl Med 49:158-163, 2008.

  8. The dock and lock method: a novel platform technology for building multivalent, multifunctional structures of defined composition with retained bioactivity. C.H. Chang, E.A. Rossi, D.M. Goldenberg. Clin Cancer Res 13:5586s-5591s, 2007.

  9. Stably tethered multifunctional structures of defined composition made by the dock and lock method for use in cancer targeting. E.A. Rossi, D.M. Goldenberg, T.M. Cardillo, W.J. McBride, R.M. Sharkey, C.H. Chang. Proc Natl Acad Sci USA 103:6841-6846, 2006.


Immunomedics - Physicians