Investigation of the therapeutic potential of recombinant bispecific bivalent anti-PD-L1/VEGF nanobody in inhibition of angiogenesis

Eskafi, Ayda Hassanzadeh; Oghalaei, A; Mahboudi, F; Ghaderi, Hajarsadat; Behdani, Mahdi; Shoari, Alireza; Kazemi‐Lomedasht, Fatemeh

doi:10.1080/08923973.2022.2131571

Cited by 9 publications

(4 citation statements)

References 29 publications

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“…An additional disadvantage of IgG-based compounds is that they may be subject to intellectual property barriers (which is less likely for the DuRan-Bis construct). Other bi-specific proteins composed of single chains that have been described in the literature include a diabody (BsDb) comprising two fused single chains targeting VEGF165 and PD1 60 and a bivalent anti-PD-L1/VEGF nanobody 61 . These proteins are smaller than our bi-specific DuRan-Bis protein, which may be advantageous in terms of tissue penetration.…”

Section: Discussionmentioning

confidence: 99%

Developing a dual VEGF/PDL1 inhibitor based on high-affinity scFv heterodimers as an anti-cancer therapeutic strategy

Tzuri

Yegodayev

Novoplansky

et al. 2023

Sci Rep

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Cancer progression is enhanced by the interaction of programmed death-ligand 1 (PDL1), which is associated with inhibition of the immune response against tumors, and vascular endothelial growth factor (VEGF), which inhibits immune cell activity while inducing angiogenesis and proliferation of cancer cells. Dual inhibition of PDL1 and VEGF may therefore confer a synergistic anti-cancer therapeutic effect. We present a novel strategy for developing a therapeutic that simultaneously binds and inhibits both PDL1 and VEGF. We generated a bi-specific protein, designated DuRan-Bis, comprising a single chain variable fragment (scFv)-based inhibitor of PDL1 fused to an scFv-based inhibitor of VEGF, with the latter being attached to an Fc fragment. We found that DuRan-Bis binds to both PDL1 and VEGF with high affinity. Compared to treatments with mono-specific proteins, alone or in combination, the DuRan-Bis chimera showed superior inhibition of the proliferation of glioblastoma cells. In comparison to treatment with immune cells alone, a combination of immune cells with DuRan-Bis decreased the viability of head and neck cancer cells. To the best of our knowledge, this study is the first to use a single polypeptide chain scFv-scFv-Fc scaffold for engineering a high-affinity bi-specific inhibitor of PDL1 and VEGF.

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Section: Discussionmentioning

confidence: 99%

Developing a dual VEGF/PDL1 inhibitor based on high-affinity scFv heterodimers as an anti-cancer therapeutic strategy

Tzuri

Yegodayev

Novoplansky

et al. 2023

Sci Rep

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“…To overcome immunotherapy tumor resistance and relapse, a bispecific anti-PD-L1/VEGF VHH was also designed. It exhibited efficient inhibition of cell proliferation and progression of angiogenesis in vitro and ex ovo, which is encouraging for future cancer therapies [132].…”

Section: Nanobody ® Molecules In Oncologymentioning

confidence: 94%

NANOBODY® Molecule, a Giga Medical Tool in Nanodimensions

Kunz,

Durandy,

Seguin

et al. 2023

IJMS

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Although antibodies remain the most widely used tool for biomedical research, antibody technology is not flawless. Innovative alternatives, such as Nanobody® molecules, were developed to address the shortcomings of conventional antibodies. Nanobody® molecules are antigen-binding variable-domain fragments derived from the heavy-chain-only antibodies of camelids (VHH) and combine the advantageous properties of small molecules and monoclonal antibodies. Nanobody® molecules present a small size (~15 kDa, 4 nm long and 2.5 nm wide), high solubility, stability, specificity, and affinity, ease of cloning, and thermal and chemical resistance. Recombinant production in microorganisms is cost-effective, and VHH are also building blocks for multidomain constructs. These unique features led to numerous applications in fundamental research, diagnostics, and therapy. Nanobody® molecules are employed as biomarker probes and, when fused to radioisotopes or fluorophores, represent ideal non-invasive in vivo imaging agents. They can be used as neutralizing agents, receptor-ligand antagonists, or in targeted vehicle-based drug therapy. As early as 2018, the first Nanobody®, Cablivi (caplacizumab), a single-domain antibody (sdAb) drug developed by French pharmaceutical giant Sanofi for the treatment of adult patients with acquired thrombocytopenic purpura (aTTP), was launched. Nanobody® compounds are ideal tools for further development in clinics for diagnostic and therapeutic purposes.

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“…Hassanzadeh et al . constructed a bivalent anti-PD-L1 × VEGF nanobody, which demonstrated efficient inhibition of angiogenesis in vitro [ 96 ]. Besides, the BsAb HB0025, targeting PD-L1 and VEGF, was developed using mAb-Trap technology.…”

Section: Anti-vegf/pd-1 and Anti-vegf/pd-l1 Bsabmentioning

confidence: 99%

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

Li,

Niu,

Zhou

et al. 2024

Cell Commun Signal

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

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Investigation of the therapeutic potential of recombinant bispecific bivalent anti-PD-L1/VEGF nanobody in inhibition of angiogenesis

Cited by 9 publications

References 29 publications

Developing a dual VEGF/PDL1 inhibitor based on high-affinity scFv heterodimers as an anti-cancer therapeutic strategy

Developing a dual VEGF/PDL1 inhibitor based on high-affinity scFv heterodimers as an anti-cancer therapeutic strategy

NANOBODY® Molecule, a Giga Medical Tool in Nanodimensions

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

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