Treating Drug-Resistant Lung Cancer Using a Combination of Antibodies

  • Yeda
  • From Israel
  • Responsive
  • Patents for licensing

Summary of the technology

A novel method to treat tyrosine kinase inhibitor (TKI) resistant cancer by using a combination of three antibodies that target EGFR (ERBB1), HER2 (ERBB2), and HER3 (ERBB3) receptors.


Background and Unmet Need

The ErbB/HER family of receptor tyrosine kinases includes epidermal growth factor receptor (EGFR, also termed ErbB-1, HER1), HER2 (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4). The ErbB/HER family members and their multiple ligand molecules form a layered signaling network, which is implicated in several human cancers. ErbB activation leads to downstream stimulation of several signaling cascades that influence cell proliferation, angiogenesis, invasion, and metastasis. Because of their oncogenic potential and accessibility, ErbB/HER proteins have emerged as attractive targets for pharmaceutical interventions, mainly tyrosine kinase inhibitors (TKIs) and anti-HER monoclonal antibodies (mABs). However, while many cancer patients were found to be sensitive to ErbBtargeted therapy, many other patients are resistant to treatment, and even among the initially responsive patients a large percentage experience tumor recurrence and become resistant to therapy. Thus, for example, despite initial dramatic response of non-small cell lung cancer (NSCLC) patients to TKIs, all patients acquire resistance within approximately one year, commonly due to malignant cells acquiring resistance through new mutations in receptors that block the effects of TKIs. Therefore, there is a need for an effective treatment against TKI resistant lung cancer.

The Solution

The team of Prof. Yosef Yarden have discovered that using a triple mAb combination targeting three HER family receptors (EGFR, HER1, and HER2) prevented the activation of downstream kinase cascades, accelerated the degradation of the receptors, and inhibited the proliferation of tumor cells but not of normal cells. This treatment can be used to treat AKI - resistant tumors as well as augment TKI dependent therapies.

Technology Essence

The team of Prof. Yarden discovered feedback regulatory loops that increase the abundance of HER2 and HER3, and activate another receptor tyrosine kinase, MET, in response to antibody-induced blockade of EGFR. The team found that using mAbs inhibiting HER2 and HER3 along with EGFR, could effectively abrogate the compensatory mechanism and inhibit NSCLC cell growth.

Applications and Advantages

  • A novel treatment for TKI resistant tumors.
  • A feasible pharmacological option for treating numerous lung cancer patients who will inevitably develop resistance to the currently applied inhibitors of EGFR.
  • In contrast to TKIs, mAbs offer target destruction, high specificity, and the ability to cooperate with chemotherapy.
  • mAbs targeting ErbB/HER receptors already exist with clinical approval.

The research team tested the concept on two TKI resistant NSCLC cell lines, H1975 and PC9ER, using different combinations of anti-EGFR (1), HER2 (2), and HER3 (3) antibodies. The tests also used a combination of the TKI erlotinib (Erlo) along with mAbs against HER2 and HER3 for comparison. Both TKI resistant cell lines tested had the greatest inhibitory effect when using a of three antibodies targeting different receptors simultaneously.

Additionally, the triple mAb combination treatment was tested in animal models comprising xenografts of NSCLC cells (H1975) grown in mice. Figure 1 exhibits that only the combination of antibodies targeting all three receptor tyrosine kinases (EGFR, HER2, and HER3) inhibited tumor progression.

Figure 1: Tumor growth of xenografted H1975 cells in CD1-nu/nu mice. Each mouse was treated every three days with either a single, double, or triple mAb treatment of (1) EGFR, (2) HER2 , or/and (3) HER3. Image modified from Mancini et al. Sci. Signal. 2015.

Intellectual property status

  • Granted Patent
  • Patent application number :USA Granted: 10,526,416 USA Granted: 10,011,659

Related Keywords

  • Biological Sciences
  • Medicine, Human Health
  • Clinical Research, Trials
  • Medical Research
  • Biology / Biotechnology
  • Cellular and Molecular Biology Technology
  • Pharmaceuticals/fine chemicals

About Yeda

Yeda ("Knowledge" in Hebrew) Research and Development Company Ltd. is the commercial arm of the Weizmann Institute of Science (WIS) and is the second company of its kind established in the world.

WIS is one of the world’s leading multidisciplinary basic research institutions in the natural and exact sciences. It is located in Rehovot, Israel, just south of Tel Aviv. It was initially established as the Daniel Sieff Institute in 1934, by Israel and Rebecca Sieff of London in memory of their son Daniel. In 1949, it was renamed for Dr. Chaim Weizmann, the first President of the State of Israel and Founder of the Institute.

Yeda initiates and promotes the transfer to the global marketplace of research findings and innovative technologies developed by WIS scientists. Yeda holds an exclusive agreement with WIS to market and commercialize its intellectual property and generate income to support further research and education.

Since 1959 Yeda has generated the highest income per researcher compared to any other TTO worldwide. Weizmann has generated a number of groundbreaking therapies, such as Copaxone, Rebif, Tookad, Erbitux, Vectibix, Protrazza, Humira, and recently the CAR-T cancer therapy Yescarta.

Yeda performs the following activities:

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