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MMP-14 Antibodies as Novel Therapeutics for Metastatic Cancers

Novel synthetic antibody that limits tumor progression and metastasis

Cancer cells illustration
Source: Design Cells, stock.adobe.com

Background

Metastasis is the leading cause of cancer related deaths. During metastasis tumor cells degrade the basement membrane of blood vessels allowing cancer cells to enter blood vessels and spread to other tissues. Tissue invasion requires matrix metalloproteinase 14 (MMP14/MT1-MMP) which is linked to poor prognosis. More than 50 small molecule MMP inhibitors have failed in cancer clinical trials due to poor specificity and toxicity.

Technology Overview

Queen’s researchers have identified several novel synthetic MMP14 antibodies by phage display screening using the MMP14 extracellular domain (ECD). A lead antibody (Fab 3369) inhibits MMP14 protease activity both in vitro and in metastatic cancer cells. The human IgG1 form of this antibody was effective at limiting TNBC tumor growth and metastasis in mouse models and limiting tumor progression and metastasis. Affinity maturation of anti-MMP-14 antibodies is currently underway.

MDA-Src cells seeded on TRITC-gelatin-coated coverslips
MDA-Src cells were seeded on TRITC-gelatin-coated coverslips and treated with or without Fab 3369 (500 nM) for 8 hours. Ab 3369 treatment of invasive human breast cancer cells blocked degradation of surrounding ECM _in cellulo_

 

MMP-14 blockade with AB 3369 inhibits breast tumor growth graphs
MMP-14 blockade with AB 3369 inhibits breast tumor growth _in vivo_. MDA-MB-231 breast tumor xenograft experiments were performed. Mice were treated with control or IgG 3369 (5 mg/kg, intraperitoneal injections, 3 times/week). Calipers were used to measure tumor volumes (left), and final tumor mass was weighed at endpoint (right; note that shRNA knock-down of MMP14 (KD) was included as a comparison to Ab 3369 blockade).

 

Lung tissue sections from MDA-MB-231 tumor-bearing mice.
 Blockade or knockdown of MMP-14 reduced lung metastasis _in vivo_. Lung tissue sections from MDA-MB-231 tumor-bearing mice. 

 

MMP-14 blockade reduces breast tumor growth and metastasis graphs
 MMP-14 blockade reduces breast tumor growth and metastasis in an immune competent breast tumor model. Orthotopic engraftment of 4T1 mouse mammary carcinoma cells in Balb-c mice. 

 

Publication Links

Benefits

This highly selective inhibitory antibody to MMP-14 overcomes the selectivity and toxicity issues of other small molecule inhibitors.

Applications

MMP-14 has a role in several disease states including preeclampsia, urinary bladder cancer, ovarian cancer, breast cancer, colorectal cancer, gastric cancer, epithelial skin cancers and fibrotic diseases.

Patents

  • No patent applications have yet been filed and antibody sequences have not been disclosed

IP Status

No patent

Seeking

  • Development partner
  • Commercial partner
  • Licensing
  • Seeking investment

Posted

April 12, 2022