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    Home > Active Ingredient News > Antitumor Therapy > New Drug Development: Anti-HER3 Targeted Therapy 30 Years of Creeping Road

    New Drug Development: Anti-HER3 Targeted Therapy 30 Years of Creeping Road

    • Last Update: 2021-03-27
    • Source: Internet
    • Author: User
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    HER3 is a member of the human epidermal growth factor receptor (HER) family, which also includes HER1/EGFR/ErbB1, HER2/ErbB2, HER4/ErbB4.

    Although HER3 has been discovered more than 30 years ago, no therapeutic interventions targeting HER3 targets have been clinically approved so far.

    With the deepening of research, more and more evidences show the importance of HER3 targets, so this article mainly summarizes the progress of HER3 targets and drugs.

    HER3: The "freak" in the family.
    HER3 is the only member of the HER family that lacks or has almost no intrinsic activity of tyrosine kinases.
    It needs to form heterodimers with other receptors HER1, HER2 or HER4 to function.

    In recent years, studies have found that HER3 often co-expresses with other receptor tyrosine kinases (RTK) in cancer cells and forms heterodimers, which activate oncogenic signaling pathways, especially PI3K/Akt, MAPK/ERK and JAK/STAT pathways and Src kinase.

    Compared with other family members, HER3 alone is not carcinogenic when overexpressed.

    However, HER3 expression has been detected in a variety of cancers, including breast cancer, ovarian cancer, colon cancer, gastric cancer, lung cancer, skin cancer, and pancreatic cancer.
    The high expression of HER3 is also related to disease progression and/or poor prognosis.

    Research on the underlying mechanism of HER3 shows that HER3 expression leads to EGFR/HER2-TKI resistance is one of the main reasons for the failure of cancer treatment.

    The activation of HER3 signal has also been shown to promote cancer metastasis.

    In addition, the activation of HER3 mutations also highlights the role of HER3 as a direct therapeutic target.

    From monoclonal antibodies to antibody-drug conjugates Because HER3 does not have strong intracellular tyrosine kinase activity, the research on anti-tumor therapy targeting HER3 mainly focuses on monoclonal antibodies.

    Seribantumab, lumertuzumab and patritumab are the most promising monoclonal antibodies targeting HER3 in clinical trials so far.
    The results of a number of phase I studies have shown good tolerability and safety, and have now progressed to II.
    /Phase III research phase.

    Seribantumab (MM-121) is a fully human IgG2 monoclonal antibody that binds to HER3.
    It can block the binding of neuregulin (NRG) ligand to HER3, thereby preventing the HER3 signal that maintains tumor activation.
    Source or heterodimerization can block downstream signals that lead to cell growth, thereby inducing tumor cell death.

    Seribantumab has been tried as a single agent or combined with anti-EGFR antibodies, chemotherapy or PI3K inhibitors in a number of phase I and phase II clinical studies.

    The Phase II study of Seribantumab combined with paclitaxel or exemestane (aromatase inhibitor) in the treatment of ovarian cancer and breast cancer did not reach the endpoint of progression-free survival (PFS).

    However, retrospective analysis showed that PFS was significantly improved in the NRG-positive subgroup, showing the importance of screening effective populations in HER3 targeted therapy.

    A phase II clinical trial of Seribantumab as a single-agent treatment of NRG1 fusion solid tumors has started.

    In EGFR-dependent tumors, seribantumab+cetuximab±irinotecan has limited activity.

    Similarly, in the phase 1b study, the HER3-specific monoclonal antibody lumretuzumab was used in combination with the EGFR inhibitor cetuximab or erlotinib.
    Even if the toxicity is acceptable, the clinical activity in HER3-positive solid tumors is not Very ideal.

    Patritumab (U3-1287) is a fully human HER3 antibody that can inhibit the binding of HER3 to ligands.

    In HER2-positive breast cancer, the overall response rate (ORR) of patritumab combined with trastuzumab and paclitaxel was 39%.

    However, the clinical trials evaluating patritumab combined with erlotinib in the treatment of non-small cell lung cancer failed to achieve the expected clinical trial endpoints.

    Patritumab deruxtecan (U3-1402) is a new type of HER3 antibody drug conjugate (ADC), which is composed of HER3 antibody patritumab and a new topoisomerase I inhibitor DX-8951 derivative (DXd).

    Studies have shown that U3-1402 has anti-tumor activity observed in cancers with multiple EGFR TKI resistance mechanisms.

    Studies have also shown that the high expression of HER3 is related to the resistance of the HER2 drug trastuzumab, while the ADC drug U3-1402 targeting HER3 can overcome HER2 resistance.

    In addition, the study also found that U3-1402 can enhance the therapeutic effect of PD-1/PD-L1 inhibitors through immune activation.

    The pan-HER family inhibitor Sym013 is a mixture of six humanized full-length monoclonal antibodies against three targets of EGFR, HER2, and HER3, and has been shown to reduce the growth of cancer cells in vivo and in vitro.

    Compared with the single/double antibodies of the HER family, Sym013 has a broader inhibitory effect and stronger efficacy.

    Bispecific antibodies can target two different tumor-associated antigens, so they can overcome some of the problems of redundant kinase activity.

    Bispecific antibodies have been developed to simultaneously block EGFR/HER3, HER2/HER3 or HER3/IGF-1R signaling.

    Duligotuzumab (MEDH7945A) is a dual-effect antibody targeting EGFR and HER3.

    Although duligotuzumab has shown acceptable safety in a phase 2b study of head and neck cancer, and has shown certain clinical activity in combination with cisplatin/5-fluorouracil, in metastatic colorectal cancer, duligotuzumab combined with FOLFIRI and Western Compared with tuximab combined with FOLFIRI, it does not improve the prognosis of patients with RAS exon 2/3 wild-type metastatic colorectal cancer.

    Pertuzumab is a monoclonal antibody that targets HER2 and can block its activation by blocking the dimerization of the HER2 receptor.

     The ORR of Pertuzumab+lumretuzumab+paclitaxel in the first-line treatment of HER3-positive and HER2 low-expressing advanced breast cancer patients was 56%, while the ORR of lumretuzumab+paclitaxel was 39%.

     However, the scope of application of this program is relatively small, and the proportion of diarrhea above grade 3 is relatively high.

    MM-111 is a bispecific antibody against HER2/HER3 at the same time.
    In preclinical models, it can inhibit the activation of HER3 induced by regulatory proteins and slow down the growth of tumors.

    The combination of MM-111 and trastuzumab or lapatinib can further inhibit the growth of HER2 overexpressing cells.

    MCLA-128 is a bispecific antibody that targets HER2 and HER3 receptors and blocks the neuregulin signaling pathway.

    Currently being evaluated in NRG1 fusion solid tumors, all 3 patients showed tumor shrinkage.

    Emerging treatment methods Proteasome degradation has become a new treatment method, including proteolytic targeted chimera (PROTAC).

    Although PROTAC targeting HER3 has not yet been reported, monoclonal antibodies can at least achieve partial degradation of HER3.

    The HER3 targeting antibody drug NG33 has been shown to induce HER3 degradation and inhibit the growth of HER2-driven cancer cells.

    Ad-HER3-FL is a vaccine that targets HER3, which can stimulate the production of HER3-specific T cells and antibodies in a mouse model, indicating that HER3 may be a good target for anti-tumor vaccines.

     In the same study, Ad-HER3-FL was used in combination with anti-PD-1 monoclonal antibody.
    Compared with the vaccine alone, the response was significantly enhanced, but further preclinical and clinical research evaluations are still needed.

    Summary HER3 is a special member of the EGFR family.
    It not only has carcinogenic effects, but can also act synergistically with other receptors to induce tumor progression, metastasis and drug resistance.

    But so far, no HER3 targeted therapy has been approved for clinical use.

    Due to the weak activity of HER3 tyrosine kinase, the development of anti-HER3 targeted drugs mainly focuses on monoclonal antibodies or bispecific antibodies.

    In clinical trials, the safety of these antibodies is acceptable, but the efficacy of single-agent therapy is very limited, so the exploration of anti-HER3 therapy focuses on combination therapy.

    The meta-analysis indicated that NRG expression may be a predictor of the response of the HER3 monoclonal antibody.

    With the continuous exploration of the mechanism of HER3, new treatment strategies will continue to emerge.
    We believe that HER3 is a promising drug target.

    References: Heidi M.
    Haikala; Pasi A Janne.
    30 years of HER3: From basic biology to therapeutic interventions.
    Clinical Cancer Research.
    DOI: 10.
    1158/1078-0432.
    CCR-20-4465
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