The present and future of bispecific antibodies for cancer therapy

Nature Reviews Drug Discovery, Год журнала: 2024, Номер 23(4), С. 301 - 319

Опубликована: Март 6, 2024

Язык: Английский

---

Recent advances in targeted strategies for triple-negative breast cancer

Journal of Hematology & Oncology, Год журнала: 2023, Номер 16(1)

Опубликована: Авг. 28, 2023

Triple-negative breast cancer (TNBC), a highly aggressive subtype of cancer, negatively expresses estrogen receptor, progesterone and the human epidermal growth factor receptor 2 (HER2). Although chemotherapy is main form treatment for patients with TNBC, effectiveness TNBC still limited. The search more effective therapies urgent. Multiple targeted therapeutic strategies have emerged according to specific molecules signaling pathways expressed in TNBC. These include PI3K/AKT/mTOR inhibitors, Notch poly ADP-ribose polymerase antibody-drug conjugates. Moreover, immune checkpoint example, pembrolizumab, atezolizumab, durvalumab, are widely explored clinic. We summarize recent advances therapy immunotherapy aim serving as reference development individualized future.

Язык: Английский

---

Exploiting innate immunity for cancer immunotherapy

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Ноя. 27, 2023

Abstract Immunotherapies have revolutionized the treatment paradigms of various types cancers. However, most these immunomodulatory strategies focus on harnessing adaptive immunity, mainly by inhibiting immunosuppressive signaling with immune checkpoint blockade, or enhancing immunostimulatory bispecific T cell engager and chimeric antigen receptor (CAR)-T cell. Although agents already achieved great success, only a tiny percentage patients could benefit from immunotherapies. Actually, immunotherapy efficacy is determined multiple components in tumor microenvironment beyond immunity. Cells innate arm system, such as macrophages, dendritic cells, myeloid-derived suppressor neutrophils, natural killer unconventional also participate cancer evasion surveillance. Considering that cornerstone antitumor response, utilizing immunity provides potential therapeutic options for control. Up to now, exploiting agonists stimulator interferon genes, CAR-macrophage -natural therapies, metabolic regulators, novel exhibited potent activities preclinical clinical studies. Here, we summarize latest insights into roles cells discuss advances arm-targeted strategies.

Язык: Английский

---

Targeting cytokine and chemokine signaling pathways for cancer therapy

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Июль 22, 2024

Abstract Cytokines are critical in regulating immune responses and cellular behavior, playing dual roles both normal physiology the pathology of diseases such as cancer. These molecules, including interleukins, interferons, tumor necrosis factors, chemokines, growth factors like TGF-β, VEGF, EGF, can promote or inhibit growth, influence microenvironment, impact efficacy cancer treatments. Recent advances targeting these pathways have shown promising therapeutic potential, offering new strategies to modulate system, progression, overcome resistance conventional therapies. In this review, we summarized current understanding implications cytokine chemokine signaling By exploring molecules biology response, highlighted development novel agents aimed at modulating combat The review elaborated on nature cytokines promoters suppressors tumorigenesis, depending context, discussed challenges opportunities presents for intervention. We also examined latest advancements targeted therapies, monoclonal antibodies, bispecific receptor inhibitors, fusion proteins, engineered variants, their metastasis, microenvironment. Additionally, evaluated potential combining therapies with other treatment modalities improve patient outcomes. Besides, focused ongoing research clinical trials that pivotal advancing our application cytokine- chemokine-targeted patients.

Язык: Английский

---

Synergistic efficacy of simultaneous anti-TGF-β/VEGF bispecific antibody and PD-1 blockade in cancer therapy

Journal of Hematology & Oncology, Год журнала: 2023, Номер 16(1)

Опубликована: Авг. 12, 2023

Recently, therapeutic antibodies against programmed cell death 1 (PD-1) and its ligand (PD-L1) have exerted potent anticancer effect in a variety of tumors. However, blocking the PD-1/PD-L1 axis alone is not sufficient to restore normal immune response. Other negative regulators antitumor immunity, like TGF-β VEGFA, are also involved escape tumor cells induce immunotherapy resistance.We developed novel anti-TGF-β/VEGF bispecific antibody Y332D based on Nano-YBODY™ technology platform. The CCK-8, flow cytometry, SBE4 luciferase reporter assay, western blotting transwell assays were used measure biological activities anti-TGF-β moiety. NFAT luminescent viability assay tube formation anti-VEGF vivo efficacy or combination with PD-1 blockade was evaluated H22, EMT-6, 4T1, AKT/Ras-driven murine hepatocellular carcinoma models. Immunofluorescent staining, RNA-seq quantitative RT-PCR adopted analyze alterations microenvironment.Y332D could maintain specific binding affinities for VEGFA. almost entirely counteracted vitro functions including immunosuppression, activated signaling, epithelial-mesenchymal transition (EMT), VEGF/VEGFR HUVEC proliferation formation. experiment data demonstrated that more effective inhibiting growth metastasis than monotherapies. In therapies, plus exhibited most durable effect. Mechanistically, upregulated density function tumor-infiltrating lymphocytes reinvigorated immunity.Y332D simultaneously block VEGF signalings. comparison monotherapies, combined exerts superior through improving microenvironment.

Язык: Английский

---

TGF-β signaling: critical nexus of fibrogenesis and cancer

Journal of Translational Medicine, Год журнала: 2024, Номер 22(1)

Опубликована: Июнь 26, 2024

Abstract The transforming growth factor-beta (TGF-β) signaling pathway is a vital regulator of cell proliferation, differentiation, apoptosis, and extracellular matrix production. It functions through canonical SMAD-mediated processes noncanonical pathways involving MAPK cascades, PI3K/AKT, Rho-like GTPases, NF-κB signaling. This intricate system finely tuned by interactions between plays key roles in both physiologic pathologic conditions including tissue homeostasis, fibrosis, cancer progression. TGF-β known to have paradoxical actions. Under normal conditions, promotes quiescence acting as tumor suppressor. In contrast, pathological states such inflammation cancer, it triggers that facilitate progression remodeling, thus promoting development fibrosis. Here, we detail the role fibrosis highlight potential for future theranostics targeting this pathway.

Язык: Английский

---

PCSK9 Inhibitors in Cancer Patients Treated with Immune-Checkpoint Inhibitors to Reduce Cardiovascular Events: New Frontiers in Cardioncology

Cancers, Год журнала: 2023, Номер 15(5), С. 1397 - 1397

Опубликована: Фев. 22, 2023

Cancer patients treated with immune checkpoint inhibitors (ICIs) are exposed to a high risk of atherosclerosis and cardiometabolic diseases due systemic inflammatory conditions immune-related atheroma destabilization. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is key protein involved in metabolism low-density lipoprotein (LDL) cholesterol. PCSK9 blocking agents clinically available involve monoclonal antibodies, SiRNA reduces LDL levels high-risk atherosclerotic cardiovascular disease events multiple patient cohorts. Moreover, induces peripheral tolerance (inhibition cancer cell- recognition), cardiac mitochondrial metabolism, enhances cell survival. The present review summarizes the potential benefits inhibition through selective antibodies siRNA cancer, especially those ICIs therapies, order reduce potentially improve ICIs-related anticancer functions.

Язык: Английский

---

Hypoxia: syndicating triple negative breast cancer against various therapeutic regimens

Frontiers in Oncology, Год журнала: 2023, Номер 13

Опубликована: Июль 10, 2023

Triple-negative breast cancer (TNBC) is one of the deadliest subtypes (BC) for its high aggressiveness, heterogeneity, and hypoxic nature. Based on biological clinical observations TNBC related mortality very worldwide. Emerging studies have clearly demonstrated that hypoxia regulates critical metabolic, developmental, survival pathways in TNBC, which include glycolysis angiogenesis. Alterations to these accelerate stem cells (CSCs) enrichment immune escape, further lead tumor invasion, migration, metastasis. Beside this, also manipulates epigenetic plasticity DNA damage response (DDR) syndicate progression. Hypoxia fundamentally creates low oxygen condition responsible alteration Hypoxia-Inducible Factor-1alpha (HIF-1α) signaling within microenvironment, allowing tumors survive making them resistant various therapies. Therefore, there an urgent need society establish target-based therapies overcome resistance limitations current treatment plan TNBC. In this review article, we thoroughly discussed plausible significance HIF-1α as a target therapeutic regimens such chemotherapy, radiotherapy, immunotherapy, anti-angiogenic therapy, adjuvant therapy photodynamic adoptive cell combination therapies, antibody drug conjugates vaccines. Further, reviewed here intrinsic mechanism existing issues targeting while improvising strategies. This highlights discusses future perspectives major alternatives by hypoxia-induced signaling.

Язык: Английский

---

The enhanced antitumor activity of bispecific antibody targeting PD-1/PD-L1 signaling

Cell Communication and Signaling, Год журнала: 2024, Номер 22(1)

Опубликована: Март 12, 2024

Abstract The programmed cell death 1 (PD-1) signaling pathway, a key player in immune checkpoint regulation, has become focal point cancer immunotherapy. In the context of cancer, upregulated PD-L1 on tumor cells can result T exhaustion and evasion, fostering progression. advent PD-1/PD-L1 inhibitor demonstrated clinical success by unleashing from exhaustion. Nevertheless, challenges such as resistance adverse effects have spurred exploration innovative strategies, with bispecific antibodies (BsAbs) emerging promising frontier. BsAbs offer multifaceted approach to immunotherapy simultaneously targeting other regulatory molecules. We focus recent advancements therapy particular emphasis development potential BsAbs, especially solid tumors. Various BsAb products PD-1 are discussed, highlighting their unique mechanisms action therapeutic potential. Noteworthy examples include anti-TGFβ × PD-L1, anti-CD47 anti-VEGF anti-4-1BB anti-LAG-3 anti-PD-1 CTLA-4 BsAbs. Besides, we summarize ongoing studies evaluating efficacy safety these agents. By unraveling intricacies microenvironment harnessing synergistic anti-PD-1/PD-L1 there exists elevate precision immunotherapy, ultimately enabling personalized treatment strategies tailored individual patient profiles.

Язык: Английский

---

Crosstalk of pyroptosis and cytokine in the tumor microenvironment: from mechanisms to clinical implication

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Ноя. 30, 2024

In the realm of cancer research, tumor microenvironment (TME) plays a crucial role in initiation and progression, shaped by complex interactions between cells surrounding non-cancerous cells. Cytokines, as essential immunomodulatory agents, are secreted various cellular constituents within TME, including immune cells, cancer-associated fibroblasts, themselves. These cytokines facilitate intricate communication networks that significantly influence initiation, metastasis, suppression. Pyroptosis contributes to TME remodeling promoting release pro-inflammatory sustaining chronic inflammation, impacting processes such escape angiogenesis. However, challenges remain due interplay among cytokines, pyroptosis, along with dual effects pyroptosis on progression therapy-related complications like cytokine syndrome. Unraveling these complexities could strategies balance inflammatory responses while minimizing tissue damage during therapy. This review delves into crosstalk elucidating their contribution metastasis. By synthesizing emerging therapeutic targets innovative technologies concerning this aims provide novel insights enhance treatment outcomes for patients.

Язык: Английский

---