Envafolimab: First Approval

Markham, Anthony

doi:10.1007/s40265-022-01671-w

Cited by 70 publications

(32 citation statements)

References 10 publications

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“…In contrast, the low immunogenicity and clinical potential of VHHs in patients have been demonstrated extensively, and currently multiple VHH-based drugs are on the marked. Caplacizumab (bivalent VHH targeting von Willebrand factor) was first approved by EMA in 2018 and later by the FDA in 2019 [ 19 – 21 ], ciltacabtagene autoleucel (CAR T-cell therapy that uses two VHHs against two different epitopes of the B-cell maturation antigen (BCMA) as targeting moieties) recently got approval of the FDA [ 22 ], envafolimab (anti-PDL1 VHH fused to the Fc domain of human IgG1) has been approved for clinical use in 2021 by the Chinese National Medical Products Administration [ 23 ] and Taisho Pharmaceutical recently filed for regulatory approval of ozoralizumab (trivalent VHH with two VHHs targeting TNF and one serum albumin for half-life extension) in Japan [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

VHHs as tools for therapeutic protein delivery to the central nervous system

Wouters

Jaspers²,

Rué³

et al. 2022

Fluids Barriers CNS

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Background The blood brain barrier (BBB) limits the therapeutic perspective for central nervous system (CNS) disorders. Previously we found an anti-mouse transferrin receptor (TfR) VHH (Nb62) that was able to deliver a biologically active neuropeptide into the CNS in mice. Here, we aimed to test its potential to shuttle a therapeutic relevant cargo. Since this VHH could not recognize the human TfR and hence its translational potential is limited, we also aimed to find and validate an anti-human transferrin VHH to deliver a therapeutic cargo into the CNS. Methods Alpaca immunizations with human TfR, and subsequent phage selection and screening for human TfR binding VHHs was performed to find a human TfR specific VHH (Nb188). Its ability to cross the BBB was determined by fusing it to neurotensin, a neuropeptide that reduces body temperature when present in the CNS but is not able to cross the BBB on its own. Next, the anti–β-secretase 1 (BACE1) 1A11 Fab and Nb62 or Nb188 were fused to an Fc domain to generate heterodimeric antibodies (1A11AM-Nb62 and 1A11AM-Nb188). These were then administered intravenously in wild-type mice and in mice in which the murine apical domain of the TfR was replaced by the human apical domain (hAPI KI). Pharmacokinetic and pharmacodynamic (PK/PD) studies were performed to assess the concentration of the heterodimeric antibodies in the brain over time and the ability to inhibit brain-specific BACE1 by analysing the brain levels of Aβ1–40. Results Selections and screening of a phage library resulted in the discovery of an anti-human TfR VHH (Nb188). Fusion of Nb188 to neurotensin induced hypothermia after intravenous injections in hAPI KI mice. In addition, systemic administration 1A11AM-Nb62 and 1A11AM-Nb188 fusions were able to reduce Aβ1-40 levels in the brain whereas 1A11AM fused to an irrelevant VHH did not. A PK/PD experiment showed that this effect could last for 3 days. Conclusion We have discovered an anti-human TfR specific VHH that is able to reach the CNS when administered systemically. In addition, both the currently discovered anti-human TfR VHH and the previously identified mouse-specific anti-TfR VHH, are both able to shuttle a therapeutically relevant cargo into the CNS. We suggest the mouse-specific VHH as a valuable research tool in mice and the human-specific VHH as a moiety to enhance the delivery efficiency of therapeutics into the CNS in human patients.

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Section: Introductionmentioning

confidence: 99%

VHHs as tools for therapeutic protein delivery to the central nervous system

Wouters

Jaspers²,

Rué³

et al. 2022

Fluids Barriers CNS

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“…Immune checkpoint blockade (ICB) therapy eradicates tumour cells via releasing the brake on the adaptive immune response and has revolutionized clinical treatments for multiple malignancies ( Deng and Zhang, 2018 ; Bagchi et al, 2021 ). To date, 18 immune checkpoint inhibitors (ICIs) have been approved as cancer therapeutics, including 12 programmed cell death protein 1 (PD-1) monoclonal antibodies (pembrolizumab, nivolumab, cemiplimab, toripalimab, sintilimab, camrelizumab, tislelizumab, zimberelimab, penpulimab, dostarlimab, serplulimab and prolgolimab), five programmed cell death ligand 1 (PD-L1) monoclonal antibodies (atezolizumab, durvalumab, avelumab, envafolimab and sugemalimab), and one monoclonal antibody that blocks cytotoxic T-lymphocyte associated protein 4 (ipilimumab) ( Dhillon, 2021 ; Dhillon and Duggan, 2022 ; Lee, 2022 ; Markham, 2022 ; Yi et al, 2022 ). Despite considerable advancements, the response rate to ICIs is currently limited to 10%–25% in most tumour types ( Schoenfeld and Hellmann, 2020 ), and those with deficient immunogenic epitopes (low mutational burden) ( Verdegaal et al, 2016 ; Tran et al, 2017 ), impoverished tumour-infiltrating lymphocytes ( Galluzzi et al, 2018 ; Fanale et al, 2022 ), or profuse immunosuppressive factors (such as PD-L1, CD73, and indoleamine 2,3-dioxygenase 1) ( Young et al, 2016 ; Chen and Mellman, 2017 ; Song et al, 2021 ) are less likely to respond ( Galluzzi et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Role of histone methyltransferase SETDB1 in regulation of tumourigenesis and immune response

Zhao

Peng

et al. 2022

Front. Pharmacol.

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Epigenetic alterations are implicated in tumour immune evasion and immune checkpoint blockade (ICB) resistance. SET domain bifurcated histone methyltransferase 1 (SETDB1) is a histone lysine methyltransferase that catalyses histone H3K9 di- and tri-methylation on euchromatin, and growing evidence indicates that SETDB1 amplification and abnormal activation are significantly correlated with the unfavourable prognosis of multiple malignant tumours and contribute to tumourigenesis and progression, immune evasion and ICB resistance. The main underlying mechanism is H3K9me3 deposition by SETDB1 on tumour-suppressive genes, retrotransposons, and immune genes. SETDB1 targeting is a promising approach to cancer therapy, particularly immunotherapy, because of its regulatory effects on endogenous retroviruses. However, SETDB1-targeted therapy remains challenging due to potential side effects and the lack of antagonists with high selectivity and potency. Here, we review the role of SETDB1 in tumourigenesis and immune regulation and present the current challenges and future perspectives of SETDB1 targeted therapy.

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“…Moreover, envafolimab (KN035) is the first PD-L1 nanobody to enter clinical development [ 45 ]. Based on the results of a pivotal phase II trial (ClinicalTrials.gov, NCT03667170), envafolimab was approved by the National Food and Drug Administration of China in November 2021, for the treatment of adult patients with previously-treated microsatellite instability-high (MSI-H) or deficient MisMatch Repair (dMMR) advanced solid tumours [ 46 ]. In addition, due to the unique structure of nanobodies, envafolimab is administered by subcutaneous injection (SC), which can improve patient compliance.…”

Section: Discussionmentioning

confidence: 99%

Tumour inhibitory activity on pancreatic cancer by bispecific nanobody targeting PD-L1 and CXCR4

Hao

et al. 2022

BMC Cancer

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Background: Antibodies and derivative drugs targeting immune checkpoints have been approved for the treatment of several malignancies, but there are fewer responses in patients with pancreatic cancer. Here, we designed a nanobody molecule with bi-targeting on PD-L1 and CXCR4, as both targets are overexpressed in many cancer cells and play important roles in tumorigenesis. We characterized the biochemical and anti-tumour activities of the bispecific nanobodies in vitro and in vivo. Methods: A nanobody molecule was designed and constructed. The nanobody sequences targeting PD-L1 and CXCR4 were linked by the (G4S)3 flexible peptide to construct the anti-PD-L1/CXCR4 bispecific nanobody. The bispecific nanobody was expressed in E. coli cells and purified by affinity chromatography. The purified nanobody was biochemically characterized by mass spectrometry, Western blotting and flow cytometry to confirm the molecule and its association with both PD-L1 and CXCR4. The biological function of the nanobody and its anti-tumour effects were examined by an in vitro tumour cell-killing assay and in vivo tumour inhibition in mouse xenograft models. Results: A novel anti-PD-L1/CXCR4 bispecific nanobody was designed, constructed and characterized. The molecule specifically bound to two targets on the surface of human cancer cells and inhibited CXCL12-induced Jurkat cell migration. The bispecific nanobody increased the level of IFN-γ secreted by T-cell activation. The cytotoxicity of human peripheral blood mononuclear cells (hPBMCs) against pancreatic cancer cells was enhanced by the molecule in combination with IL-2. In a human pancreatic cancer xenograft model, the anti-PD-L1/CXCR4 nanobody markedly inhibited tumour growth and was superior to the combo-treatment by anti-PD-L1 nanobody and anti-CXCR4 nanobody or treatment with atezolizumab as a positive control. Immunofluorescence and immunohistochemical staining of xenograft tumours showed that the anti-tumour effects were associated with the inhibition of angiogenesis and the infiltration of immune cells. Conclusion: These results clearly revealed that the anti-PD-L1/CXCR4 bispecific nanobody exerted anti-tumour efficacy in vitro and inhibited tumour growth in vivo. This agent can be further developed as a therapeutic reagent to treat human pancreatic cancer by simultaneously blocking two critical targets.

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Envafolimab: First Approval

Cited by 70 publications

References 10 publications

VHHs as tools for therapeutic protein delivery to the central nervous system

VHHs as tools for therapeutic protein delivery to the central nervous system

Role of histone methyltransferase SETDB1 in regulation of tumourigenesis and immune response

Tumour inhibitory activity on pancreatic cancer by bispecific nanobody targeting PD-L1 and CXCR4

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