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    Home > Active Ingredient News > Antitumor Therapy > Research advances in targeted therapy for tumoroglycans

    Research advances in targeted therapy for tumoroglycans

    • Last Update: 2022-09-14
    • Source: Internet
    • Author: User
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    preface

    Glycosylation, a complex form of post-translational modification that affects more than 50% of cellular proteins, is a key regulator of many eukaryotical processes


    Different abnormal glycosylation mechanisms lead to the formation of tumor-associated glycoantigens (TACA)


    For more than two decades, these TACA have shown potential application value


    Treatments involving TACA are diverse, including vaccine-induced active immunity, as well as genetically engineered monoclonal antibodies


    Target sphingosine glycolipids

    Sphingosine glycolipids (GSL) consist of a heterogeneous membrane lipid formed


    The main GSLs characterized by TACA include Globo H, SSEA-3, and SSEA-4, as well as sphingosines containing sialic acid, such as gangliosides GD2, GD3, GM2, fucoidyl GM1, and Neu5GCM3


    GD2

    Ganglioside GD2 is an N-acetyl-neuranine-containing glycolipid antigen consisting of 5 monosaccharides anchored to


    GD2 expression levels are low in normal tissues, but in various types of cancers such as neuroblastoma, small cell lung cancer, melanoma, glioma, and sarcoma, the expression of this weak immunogenic antigen can reach 107 molecules


    Several anti-GD2 monoclonal antibodies have been successfully tested in clinical practice, including CH 14.


    BsAbs, which target GD2, have broad


    With regard to the tumor vaccine for GD2, a bivalent vaccine containing GD2 and GD3 linked to KLH was evaluated for the first time in a phase I trial in patients with high-risk neuroblastoma, with OPT-821 as an adjuvant


    GD3

    GD3 is another highly expressed bisialic acid ganglioside in cancers of neuroectodermal origin


    Regarding vaccine strategies, a unique monoclonal antibody (BEC2) against R24 with good properties has been developed and confirmed that BEC2 can mimic GD3 gangliosides and induce anti-GD3 IgG


    Fucoidyl-GM1

    Ganglioside fucoidosyl-GM1 (FucGM1) is a tumor-associated antigen that is highly expressed in most human small cell lung cancers but is absent in most normal adult tissues, making FucGM1 an attractive target


    Recently, a new non-fucosylated fully human IgG1 antibody (BMS-986012) was developed that is specific


    GM3

    Ganglioside GM3 is widely distributed in almost all types of animal cells and is overexpressed in several human cancers, such as melanoma, lung cancer, and brain cancer


    One strategy for vaccine development is to form small-size protein liposomes (VSSPs) (GlycoVaxGM3-NeuGcGM3/VSSP) from the hydrophobic outer membrane protein of Neisseria meningitidis containing GM3
    .
    This vaccine is reported to be safe and immunogenic
    .
    In patients with melanoma, the GlycoVaxGM3 vaccine improves overall survival in patients with metastasis after first-line chemotherapy
    .
    Patients with metastatic breast cancer were also evaluated for clinical efficacy of Glyco VaxGM3, with higher
    overall survival rates in vaccinated patients.

    In addition, promising results were achieved against the unique type of vaccine Racotumomab (Vaxira: registered:), which mimics ganglioside GM3
    .
    A Phase I clinical trial of Racotumomab (NCT01598454) was conducted in a pediatric patient with cancer expressing N-glycosylated gangliosides, which confirmed its good safety and triggered an immune response
    in most patients.
    Currently, a phase II trial (NCT02998983)
    is currently being conducted in patients with high-risk neuroblastoma.
    Currently, Vaxira:registered:has entered the market as the first approved anti-unique vaccine (in Argentina and Cuba) as an active immunotherapy agent
    for advanced NSCLC therapy.
    The study found that the Racotumomab vaccine-induced anti-GM3 antibody can mediate the antigen-specific ADCC response
    of NSCLC patients against tumor cells.
    Similarly, an immune response
    that produces IFN-γ is found in patients treated with Metastatic breast cancer treated with Vaxira:registered.

    Globo series

    The Globo family of GSLs, such as stage-specific embryonic antigen 3 (SSEA-3), SSEA-4, and globo-H, are specifically expressed
    on pluripotent stem cells and cancer cells.
    Among them, the most common cancer-related antigen is Globo-H ceramide (GHCer), which is overexpressed in several cancers, including breast, stomach, lung, ovarian, endometrial, pancreatic, and prostate cancers
    .

    GHCer-targeted immunotherapy for breast cancer has yielded encouraging results, and in two Phase I clinical trials in patients with recurrent prostate and metastatic breast cancer, a vaccine containing the Globo H–KLH conjugate and immune adjuvant QS-21 has been shown to be safe while also inducing humoral immune responses
    .
    Currently, a global phase III trial for triple-negative breast cancer is underway (NCT03562637
    ).

    In addition, a new antibody-conjugated drug (OBI-999) derived from an anti-Globo-H monoclonal antibody, coupled to MMAE, exhibited good tumor suppressor effects
    in different animal models.
    Two Phase I/II clinical trials are currently underway to evaluate the safety, pharmacodynamics, and therapeutic activity of antiglobo-H monoclonal antibody OBI-888 in multiple advanced and metastatic solid tumors (NCT03573544), and the safety, pharmacodynamics, and therapeutic activity
    of ADC OBI-999 in advanced solid tumors (NCT04084366).

    Targets mucin-type O-glycan antigens

    Simple mucin-type O-glycosylated TACA, such as Tn antigen (CD175), TF antigen (CD176), and sialic acid Tn antigen (STn, CD175s), are very attractive targets for antitumor therapies because they are detected in most cancers and are usually absent
    in healthy tissue.

    Tn antigen

    Using different immune strategies, several monoclonal antibodies that recognize Tn antigens have been produced, such as PankoMab, 5E5, KM3413, and 6C5
    .
    PankoMab and 5E5 specifically recognize Tn-MUC1 peptides, while 6C5 specifically recognizes Tn peptide epitopes
    in dysadherin/FXYD5.
    PankoMab GEX:trade_mark: is a fully humanized antibody derived from PankoMab that enhances Fc-mediated antitumor activity
    through glycoengineering.
    A Phase I clinical trial (NCT01222624) in patients with advanced solid tumors, primarily colon and ovarian cancers, showed that the drug was safe and well
    tolerated.
    After promising initial efficacy in patients with ovarian cancer, a Phase II study (NCT01899599) was conducted in patients with recurrent ovarian, tubal, or primary peritoneal cancer to evaluate the efficacy
    of PankoMab GEX:trade_mark: versus placebo in maintaining response after chemotherapy.
    However, the study failed to demonstrate an improvement
    in progression-free survival.
    Another solid tumor phase I trial (NCT03360734) evaluated PankoMabGEX:trade_mark:in combination with anti-EGFR antibodies, demonstrating its feasibility and antitumor activity
    in patients with colorectal cancer (CRC) and non-small cell lung cancer.

    Sialic acid Tn antigen

    STn is often co-expressed with Tn, and abnormal expression of STn is associated with dysregulation of O-glycosylation mechanisms, including unbalanced expression of Cosmc and STn synthase (ST6GalNAc-I), resulting in more aggressive cancer cell behavior, reduced cell-cell aggregation, increased tumor growth, extracellular matrix adhesion, migration, invasion, and metastasis
    .

    Humanized monoclonal antibodies (huCC49) targeting sTn have been evaluated in phase I/II radioimmunotherapy clinical trials with encouraging
    results.
    177Lu-CC49 is well tolerated with intraperitoneal radioimmunotherapy and appears to have antitumor activity
    against intraperitoneal chemotherapy-resistant ovarian cancer.
    In a Phase II clinical trial, radiation immunotherapy for hormone-resistant metastatic prostate cancer enhanced tumor uptake and antitumor effects
    in combination with 131I-CC49 Phase II trials conducted separately.
    Due to prolonged plasma circulation time, dose-limiting myelotoxicity, HAMA responses are observed in most patients
    .
    To improve these problems, a CH2 domain deletion of humanized CC49 (HuCC49ΔCH2) was developed
    .
    Recently, in mouse models of radioimmunotherapy for ovarian cancer, tumor growth has been observed to be significantly reduced in a dose-dependent manner with no significant extra-target toxicity
    .
    In addition, anti-STn monoclonal antibody SF3-MMAE antibody conjugated drugs showed significant tumor growth inhibition effects in STn-expressing models of breast cancer and colon cancer xenograft cancer, with no significant toxicity
    .

    In terms of vaccines, the STn-targeted vaccine (Theratope) induces an effective antibody response in mouse breast cancer models, delaying tumor growth
    .
    However, in a large phase III clinical trial (NCT00003638) in patients with metastatic breast cancer, no overall benefit of the treatment regimen was observed, and only general clinical efficacy
    was achieved in patients with metastatic breast cancer who received endocrine therapy (NCT00046371).

    TF antigen

    TF is relatively low in many normal tissues but high in cancerous tissues, associated
    with aggressiveness, tumor growth, and high metastatic potential.

    JAA-F11 is a specific IgG3 monoclonal antibody that targets TF-α and shows the effects
    of tumor growth inhibition and lung metastasis reduction in breast cancer metastasis model 4T1.
    The humanized form of JAA-F11 (hJAA-F11) In the Xenograft model of human breast cancer in SCID mice, both the naked antibody and the ADC form (hJAA-F11-DM1) can inhibit tumor progression in vivo, but clinical trials
    of this antibody have not been conducted.

    Another monoclonal antibody (170H.
    82) can bind two forms of TF antigen and can react
    to breast, lung, and colon cancers.
    Currently, the radiolabeled m170 antibody (Y90 MOAB m170) in combination with cyclosporine and paclitaxel is being tested
    in two Phase I clinical trials for recurrent or refractory metastatic breast cancer (NCT00009763) and metastatic prostate cancer (NCT00009750) that does not respond to hormone therapy.

    In terms of vaccines, the effect of TF-KLH conjugate vaccine plus QS21 (NCT00003819)
    is being evaluated in patients with recurrent prostate cancer.
    All doses induce high titer IgM and IgG antibodies
    against TF.

    Target lewis antigens

    Type I and Type II Lewis antigens are fucosylated carbohydrate structures at the end of the blood group system of human tissues, and lewis antigens and their silicic acidified forms are largely related to disease progression and spread in cancer patients, and as cancer-associated antigens, they may become promising targets for new approaches to personalized medicine
    .

    As a therapeutic target, sialic acid LewisA (SLeA) has attracted interest and has developed fully human monoclonal antibodies that show improved
    overall survival in animal models.
    The antibody, called MVT-5873, used in combination with gemcitabine and nab paclitaxel for the evaluation of pancreatic cancer, proved its own safety and tolerability
    .
    In addition, CA19-9 positive malignancy was further evaluated in combination with FOLFIRINOX (NCT02672917
    ).
    Another antibody targeting sialic acid LewisA is FG129, whose ADC forms (DM1 and DM4) show promising results
    in preclinical models.

    In addition, anti-LeY monoclonal antibodies have also been developed and evaluated as potential cancer treatment drugs
    .
    The humanized antibody hu3S193 shows high specificity
    for LeY antigens.
    In clinical studies, it has been shown to be safe and has strong tumor-specific anti-tumor activity (NCT00084799
    ).
    However, in the Phase II study of gynecological cancers (NCT00617773), the clinical benefit of hu3S193 was shown to be modest
    .
    Recently, a novel bispecific antibody against LeY and CD3 (m3s193 BsAb) was developed that shows strong T cell recruitment and antitumor activity in animal models of gastric cancer and shows potential value
    for gastric cancer treatment.
    Another anti-LeY-specific monoclonal antibody, BR96, which was evaluated in a clinical trial (NCT00051571) with doxorubicin in combination with doxorubicin in the form of an ADC (NCT00051571) demonstrated its safety and suitability in second- and third-line therapies
    .
    In contrast, in metastatic breast cancer, its clinical antitumor activity is limited
    .

    Given the vaccine strategy, SLeA may be an interesting candidate because it is highly expressed in several epithelial malignancies but is not detected
    in the corresponding normal tissues.
    The SLeA-KLH vaccine was evaluated in a preliminary study (NCT00470574) in patients with metastatic breast cancer, and the results confirmed the safety and immunogenicity of
    the product.

    Targeted polysialic acid

    The glycan modification process connects the monomeric sialic acid body to the non-reducing end of the glycan tree, forming a polysialic acid tail (PSA
    ).
    Although PSA is almost absent in most adult tissues, it is expressed
    in the progression of some malignancies, such as neuroblastoma, breast cancer, laryngeal squamous cell carcinoma, pancreatic cancer, non-small cell lung cancer, and small cell lung cancer.
    The most important physical properties of PSA are its anti-adhesion effect, which favors invasion and metastasis, in addition, the interaction of transpsa and inhibitory siglec promotes immune escape
    of tumor cells.

    At present, several highly specific monoclonal antibodies have been developed: MY.
    1E12, OL.
    28 [, MAB735
    ].
    However, clinical trials
    for cancer treatment have not yet been conducted.
    Taking into account the vaccine, the use of N-propionylated PSA-KLH conjugate plus the immunoadjuvant QS21 in patients with small cell lung cancer was clinically validated (NCT00004249), proved safe and capable of inducing a high-titer antibody response, where 10 μg is the optimal immunogenic dose
    .
    Based on these results, N-propionylated PSA was included in a pentavalent vaccine that includes four other glycolipids overexpressed in small cell lung cancer (NCT01349647).

    CAR-T cell therapy

    CAR-T cells combine the specificity of antibodies with the cell lysis capacity of T cells in an MHC-independent manner
    .
    In this way, some TACA has been shown to have potential applications in anti-tumor CAR-T cell therapy, with the most notable advances including anti-GD2, anti-MUC1/MUC1-Tn, and anti-STn CAR-T therapy
    .

    CAR-T cells targeting GD2

    Due to the high expression and importance of GD2 in solid tumors, especially neuroblastoma, anti-GD2-CAR-T cell immunotherapy has been widely used in clinical research on neuroblastoma, and the following table lists the clinical trials of GD2-CAR-T in the past 5 years:

    To further maintain the survival of GD2-CAR T cells, additional stimulating molecules such as interleukin-15 (IL15) are incorporated into the
    CAR structure.
    GD2-CAR.
    15 T cells containing IL-15 are more effective at controlling tumor growth, with a smaller total infusion of T cells and improved survival after re-excitation experiments
    .
    Further clinical trials of GD2 CAR.
    15 T cells (NCT03294954) are underway
    .

    To improve the safety of CAR-T cell therapy, one approach is to establish inducible suicide genes
    .
    The inducible cysteine protease 9 (iCasp9) suicide gene was integrated into the CAR of GD2-CAR-T cells
    .
    iCasp9 is not toxic at the basal expression level, and small molecule dimer drugs induce cells to express iCasp9, resulting in rapid apoptosis of transduced cells
    .
    Activated CELLS expressing CAR are preferentially killed, providing a safety switch
    .

    CAR-T cells targeting MUC1/MUC1-Tn

    CAR-T cell strategies targeting MUC1/MUC1-Tn have shown encouraging results
    in preclinical studies using different in vivo cancer models.

    Clinically, phase I clinical trials using two different structures of anti-MUC1 CAR-T cells showed preliminary efficacy and safety
    in patients with metastatic seminal vesicle cancer.
    In addition, CAR-T with the same specificity but PD-1 KO was evaluated in NSCLC (NCT03525782) and the treatment proved safe and well
    tolerated.
    Currently, another MUC1 CAR-T undergoing clinical evaluation is huMNC2-CAR44 (NCT04020575).

    In addition, a multicenter clinical trial (NCT04025216) evaluating TnMUC1 CAR-T therapy for solid tumors (triple-negative breast cancer, epithelial ovarian cancer, pancreatic cancer and non-small cell lung cancer) and TnMUC1-positive multiple myeloma has yet to be evaluated
    。 Finally, a third-generation CAR-T cell targeting MUC1 was constructed, along with a variety of other targets (PSCA, TGF-β, HER2, mesothelin, LeY, GPC3, AXL, EGFR, Claudin18.
    2, or B7-H3), an interesting strategy to help overcome cancer heterogeneity, and lung cancer is currently being evaluated
    in a clinical trial (NCT03198052).

    CAR-T cells targeting STn

    CAR-T cells targeting STn showed anti-tumor activity
    in vitro and mouse xenograft models.
    In 2017, the first batch of sTn CAR-T cell treatment for solid tumors reported the results of a human clinical trial, reporting data from two studies that used first-generation CAR-T cells to target STn in patients with metastatic colorectal cancer, but neither study observed a clinical response
    .

    brief summary

    The glycan pattern expressed in cancer cells has a significant impact on tumor behavior, and the overexpression of TACA on a variety of cancer cells makes it an attractive target
    for the development of immunotherapy.
    At present, a variety of antibodies, ADCs, CAR-T and BsAb targeting TACAs have entered the clinical stage, synergistic with other anti-tumor strategies, showing strong therapeutic potential
    .

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