Unique camel-human hybrid mAbs against pro-invasive MMP-14

Institution: University of California, Riverside
Investigator(s): Xin Ge, Ph.D. -
Award Cycle: 2015 (Cycle 21) Grant #: 21IB-0104 Award: $241,174
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure



Initial Award Abstract (2015)

Accounting for over 230,000 new diagnoses and almost 40,000 casualties each year, breast cancer is one of the most common malignancy affecting American women. The leading cause of patient death is the spread, or metastasis, of tumor cells to a distant site such as the brain, the liver and the bones. During metastatic process, breast cancer cells secrete enzymes that degrade their surrounding support structure, the extracellular matrix (ECM). This allows tumor cells to penetrate through the ECM and invade into the blood and lymphatic vessels for their migration to a distant tissue. There is a consensus among professionals that invasion-promoting, protumorigenic membrane type-1 matrix metalloproteinase (MT1-MMP/MMP-14) is a promising drug target of metastasis. Of clinical importance for breast cancer, it has been demonstrated that MMP-14 promotes blood vessel invasion and distant metastasis in triple-negative (ER, PR, Her2neu) breast cancer, an aggressive breast cancer sub-type with limited treatment options. Our project is sharply focused on the design, engineering, optimization and testing of the unique human monoclonal antibodies (mAbs) capable of selectively and efficiently inhibiting pro-invasive MMP-14 in breast cancer. Our work will advance understanding of the molecular mechanism by which the breast cancer cells migrate through extracellular matrix, and more importantly provide a solid foundation for the novel therapy for triple-negative breast cancer.

The question(s) or central hypotheses of the research: We intend to determine whether specifically inhibiting MMP-14 blocks aberrant enzymatic activity and reduces or even eliminates tumor progression and metastasis in breast cancer. The central hypothesis of this IDEA project is that the highly efficient and selective anti-MMP-14 mAb inhibitors will block aberrant enzyme activity and, as a result, interfere with tumor progression and metastasis in breast cancer. The general methodology: In our previous studies, we have successfully isolated the human mAb 3A2, which inhibits MMP-14 efficiently and with high selectivity. In this project, we will further enhance 3A2’s potency by ‘directed evolution’, a technique that mimics the progress of natural evolution in test tubes but with a much faster time-frame— in weeks instead of thousands of years. More specifically, we will create millions of random mutants of 3A2 and select the ones with the strongest inhibitory and selectivity parameters. The isolated 3A2 derivatives with improved affinity will then be produced by cell culture in a scale that is required for their thorough biochemical and pre-clinical analyses. The anti-tumor potency of the 3A2 antibodies and its optimized derivatives will also be carefully assessed in the relevant assays in vitro and in vivo, using our well-established cell-based and animal tests.

Innovative elements of the project: Previous clinical trials of small-molecule synthetic MMP inhibitors failed in cancer. Now it is becoming clear that this failure is the result of the poor inhibitors’ selectivity – instead of inhibiting a single MMP these inhibitors inhibited multiple, both pro-tumorigenic and anti-tumorigenic, MMPs. In contrast, the antibody we have already developed is highly selective for a single, most important MMP in breast cancer, specifically, for protumorigenic, invasion-promoting MMP-14. Because of our unique approach and the highly promising results we already acquired, we are confident that our antibody can be a foundation for the novel and powerful therapy in breast cancer.

Publications:
Identification of highly selective MMP-14 inhibitory Fabs by deep sequencing
Active-site MMP-selective antibody inhibitors discovered from convex paratope synthetic libraries



Direct Production of Functional Matrix Metalloproteinase -14 Without Refolding or Activation and its Application for In Vitro Inhibition Assays.
Periodical:Biotechnology and Bioengineering
Index Medicus: Biotechnol Bioeng
Authors: Nam DH, Ge X
Yr: 2016 Vol: 113 Nbr: 4 Abs: Pg:717-23

Identification of Highly Selective MMP-14 Inhibitory Fabs by Deep Sequencing.
Periodical:Biotechnology and Bioengineering
Index Medicus: Biotechnol Bioeng
Authors: Lopez T, Nam DH, Kaihara E, Mustafa Z, Ge X.
Yr: 2017 Vol: 114 Nbr: 6 Abs: Pg:1140-50

Selective Function-Blocking Monoclonal Human Antibody Highlights the Important Role of Membrane Type-1 Matrix Metalloproteinase (MT1-MMP) in Metastasis.
Periodical:Oncotarget
Index Medicus:
Authors: Remacle AG, Cieplak P, Nam DH, Shiryaev SA, Ge X, Strongin AY.
Yr: 2017 Vol: 8 Nbr: Abs: Pg:2781-99