AAV9 delivered bispecific nanobody attenuates amyloid burden in the gelsolin amyloidosis mouse model

Verhelle, Adriaan; Nair, Nisha; Everaert, Inge; Overbeke, Wouter Van; Supply, Lynn; Zwaenepoel, Olivier; Peleman, Cindy; Dorpe, Jo Van; Lahoutte, Tony; Devoogdt, Nick; Derave, Wim; Chuah, Marinee; VandenDriessche, Thierry; Gettemans, Jan

doi:10.1093/hmg/ddx056

Cited by 26 publications

(12 citation statements)

References 32 publications

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“…For example, intramuscular injection of AAV encoding HIV-neutralizing antibodies or a CD4–Fc fusion protein led to long-term production of the encoded antibodies and protection of mice from HIV infection ( 131 , 132 ). In a recent proof of principle study, an AAV-encoded bispecific nanobody was effectively expressed in vivo and exhibited therapeutic efficacy in a mouse model of amyloidosis ( 133 ). It is conceivable that AAV can similarly be engineered for local and/or long-term expression of antitumor nanobodies in vivo .…”

Section: Viral and Cellular Delivery Of Antitumor Nanobodies And Heavmentioning

confidence: 99%

Nanobodies and Nanobody-Based Human Heavy Chain Antibodies As Antitumor Therapeutics

Bannas¹,

2017

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Monoclonal antibodies have revolutionized cancer therapy. However, delivery to tumor cells in vivo is hampered by the large size (150 kDa) of conventional antibodies. The minimal target recognition module of a conventional antibody is composed of two non-covalently associated variable domains (VH and VL). The proper orientation of these domains is mediated by their hydrophobic interface and is stabilized by their linkage to disulfide-linked constant domains (CH1 and CL). VH and VL domains can be fused via a genetic linker into a single-chain variable fragment (scFv). scFv modules in turn can be fused to one another, e.g., to generate a bispecific T-cell engager, or they can be fused in various orientations to antibody hinge and Fc domains to generate bi- and multispecific antibodies. However, the inherent hydrophobic interaction of VH and VL domains limits the stability and solubility of engineered antibodies, often causing aggregation and/or mispairing of V-domains. Nanobodies (15 kDa) and nanobody-based human heavy chain antibodies (75 kDa) can overcome these limitations. Camelids naturally produce antibodies composed only of heavy chains in which the target recognition module is composed of a single variable domain (VHH or Nb). Advantageous features of nanobodies include their small size, high solubility, high stability, and excellent tissue penetration in vivo. Nanobodies can readily be linked genetically to Fc-domains, other nanobodies, peptide tags, or toxins and can be conjugated chemically at a specific site to drugs, radionuclides, photosensitizers, and nanoparticles. These properties make them particularly suited for specific and efficient targeting of tumors in vivo. Chimeric nanobody-heavy chain antibodies combine advantageous features of nanobodies and human Fc domains in about half the size of a conventional antibody. In this review, we discuss recent developments and perspectives for applications of nanobodies and nanobody-based human heavy chain antibodies as antitumor therapeutics.

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Section: Viral and Cellular Delivery Of Antitumor Nanobodies And Heavmentioning

confidence: 99%

Nanobodies and Nanobody-Based Human Heavy Chain Antibodies As Antitumor Therapeutics

Bannas¹,

2017

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“…Examples hereof are fusion of the nanobody directly with albumin, polyethylene glycol (PEG; PEGylation) or IgG-Fc (allowing recycling through the neonatal Fc receptor [FcR]), or indirectly with a second nanobody that binds albumin or the neonatal FcR, thereby generating bispecific constructs 39-42. Another option to obtain maximal delivery in the tumor site is to use a gene therapy approach, which could be highly feasible for nanobodies as these are simple proteins expressed from one single gene 43,44. A continuous, local secretion of nanobodies by genetically engineered cells in the tumor microenvironment (TME) will maximize their delivery to the target of interest and will moreover minimize the risks associated with systemic distribution.…”

Section: Advantages and Disadvantages Of Nanobodiesmentioning

confidence: 99%

Theranostics in immuno-oncology using nanobody derivatives

Lecocq

Vlaeminck

Hanssens³

et al. 2019

Theranostics

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Targeted therapy and immunotherapy have become mainstream in cancer treatment. However, only patient subsets benefit from these expensive therapies, and often responses are short‐lived or coincide with side effects. A growing modality in precision oncology is the development of theranostics, as this enables patient selection, treatment and monitoring. In this approach, labeled compounds and an imaging technology are used to diagnose patients and select the best treatment option, whereas for therapy, related compounds are used to target cancer cells or the tumor stroma. In this context, nanobodies and nanobody-directed therapeutics have gained interest. This interest stems from their high antigen specificity, small size, ease of labeling and engineering, allowing specific imaging and design of therapies targeting antigens on tumor cells, immune cells as well as proteins in the tumor environment. This review provides a comprehensive overview on the state-of-the-art regarding the use of nanobodies as theranostics, and their importance in the emerging field of personalized medicine.

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“…Some groups have also used AAV vectors to express Nbs . Verhelle et al have used AAV9 to express a bispecific Nb to treat amyloidosis in a mouse model of this disease [44], and Del Rosario et al have used AAV8 to express an influenza virus neutralizing Nb fused to an Fc domain to protect mice from viral infection [45].…”

Section: Discussionmentioning

confidence: 99%

Long-Term Systemic Expression of a Novel PD-1 Blocking Nanobody from an AAV Vector Provides Antitumor Activity without Toxicity

et al. 2020

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Immune checkpoint blockade using monoclonal antibodies (mAbs) able to block programmed death-1 (PD-1)/PD-L1 axis represents a promising treatment for cancer. However, it requires repetitive systemic administration of high mAbs doses, often leading to adverse effects. We generated a novel nanobody against PD-1 (Nb11) able to block PD-1/PD-L1 interaction for both mouse and human molecules. Nb11 was cloned into an adeno-associated virus (AAV) vector downstream of four different promoters (CMV, CAG, EF1α, and SFFV) and its expression was analyzed in cells from rodent (BHK) and human origin (Huh-7). Nb11 was expressed at high levels in vitro reaching 2–20 micrograms/mL with all promoters, except SFFV, which showed lower levels. Nb11 in vivo expression was evaluated in C57BL/6 mice after intravenous administration of AAV8 vectors. Nb11 serum levels increased steadily along time, reaching 1–3 microgram/mL two months post-treatment with the vector having the CAG promoter (AAV-CAG-Nb11), without evidence of toxicity. To test the antitumor potential of this vector, mice that received AAV-CAG-Nb11, or saline as control, were challenged with colon adenocarcinoma cells (MC38). AAV-CAG-Nb11 treatment prevented tumor formation in 30% of mice, significantly increasing survival. These data suggest that continuous expression of immunomodulatory nanobodies from long-term expression vectors could have antitumor effects with low toxicity.

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AAV9 delivered bispecific nanobody attenuates amyloid burden in the gelsolin amyloidosis mouse model

Cited by 26 publications

References 32 publications

Nanobodies and Nanobody-Based Human Heavy Chain Antibodies As Antitumor Therapeutics

Nanobodies and Nanobody-Based Human Heavy Chain Antibodies As Antitumor Therapeutics

Theranostics in immuno-oncology using nanobody derivatives

Long-Term Systemic Expression of a Novel PD-1 Blocking Nanobody from an AAV Vector Provides Antitumor Activity without Toxicity

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