Research

DOCK-AND-LOCK®

Background

Together with IBC Pharmaceuticals, Inc., we have developed a new platform technology, called the DOCK-AND-LOCK® method, or DNL®, which has the potential for making a considerable number of bioactive molecules of increasing complexity. DNL® 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 DNL® is the exclusive generation of a stable complex, in a quantitative manner that retains the full biological activities of its individual components.

DNL® 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 DNL®, we have created multivalent, mono- or multi-specific antibodies; DNL-PEGylated cytokines; and cytokine-antibody conjugates.

An immunocytokine, named 20-2b, comprising veltuzumab and four copies of interferon-alpha (IFNα) was developed using DNL®. 20-2b potently kills non-Hodkin lymphoma (NHL) cells in vitro and has exhibited in-vivo activity in human NHL xenograft animal models. This novel immunocytokine is being developed as a biologic therapeutic agent for NHL with funding of a Phase II Small Business Innovation Research grant from the National Institutes of Health.

DNL® is also being used particularly to make bispecific antibodies targeting cancers and infectious diseases as a T-cell redirecting immunotherapy. This is one of several new methods of cancer immunotherapy being studied both clinically and preclinically. In contrast to hematological tumors, little progress has been made in this approach to treat the more challenging solid cancers, including pancreatic and gastric cancers, two malignancies with very high rates of mortality.

We are developing a novel investigational T-cell redirecting bispecific antibody, (E1)-3s, created using DNL® for the potential treatment of pancreatic and gastric cancers. These and various other solid cancers express high-levels of TROP-2, a target recognized by the bispecific (E1)-3s, which also binds to the CD3 antigen on T cells.

(E1)-3s effectively induced a potent and specific T-cell-mediated killing of human pancreatic and gastric cancer cell lines. Furthermore, in animal models of human pancreatic or gastric cancer, treatment with (E1)-3s significantly inhibited tumor growth, which resulted in improved survival compared with the control groups. Adding interferon-α enhanced the tumor-growth-inhibition activity of (E1)-3s.

References
  • Rossi DL, Cardillo TM, Rossi EA, Zalath M, Goldenberg DM, Chang CH. A novel Trop-2/CD3 trivalent bispecific antibody effectively redirects T cells to kill target human pancreatic and gastric cancer cells. American Association for Cancer Research (AACR) 2014 Annual Meeting, Abstr. #2655, April 7, 2014.

  • Rossi DL, Rossi EA, Cardillo TM, Goldenberg DM, Chang CH. A new class of bispecific antibodies to redirect T cells for cancer immunity. MAbs. 2014 Mar 1;6(2):381-91.

  • Rossi EA, Goldenberg DM, Chang CH. The dock-and-lock method combines recombinant engineering with site-specific covalent conjugation to generate multifunctional structures. Bioconjug Chem. 23(3):309-23, 2012.

  • Rossi EA, Goldenberg DM, Chang CH. Complex and defined biostructures with the dock-and-lock method. Trends Pharmacol Sci. 33(9):474-81, 2012.

  • Rossi EA, Rossi DL, Cardillo TM, Stein R, Goldenberg DM, Chang CH. Preclinical studies on targeted delivery of multiple IFN{alpha}2b to HLA-DR in diverse hematologic cancers. Blood 118:1877-1884, 2011.



Immunomedics - Physicians