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Live long and active: Polypeptide-mediated assembly of antibody variable fragments.

ABSTRACT: Antibodies possess multiple biologically relevant features that have been engineered into new therapeutic formats. Two examples include the adaptable specificity of their variable (Fv) region and the extension of plasma circulation times through their crystallizable (Fc) region. Since the invention of the single chain variable fragment (scFv) in 1988, antibody variable regions have been re-engineered into a wide variety of multifunctional nanostructures. Among these strategies, peptide-mediated self-assembly of variable regions through heterologous expression has become a powerful method to produce homogenous, functional biomaterials. This manuscript reviews recent reports of antibody fragments assembled through fusion with peptides and proteins, including elastin-like polypeptides (ELPs), collagen-like polypeptides (CLPs), albumin, transmembrane proteins, leucine zippers, silk protein, and viruses. This review further discusses the current clinical status of engineered antibody fragments and challenges to overcome.

SUBMITTER: Lee C

PROVIDER: S-EPMC8382037 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Live long and active: Polypeptide-mediated assembly of antibody variable fragments.

Lee Changrim C Choi Minchang M MacKay J Andrew JA

Advanced drug delivery reviews 20201028

Antibodies possess multiple biologically relevant features that have been engineered into new therapeutic formats. Two examples include the adaptable specificity of their variable (Fv) region and the extension of plasma circulation times through their crystallizable (Fc) region. Since the invention of the single chain variable fragment (scFv) in 1988, antibody variable regions have been re-engineered into a wide variety of multifunctional nanostructures. Among these strategies, peptide-mediated ...[more]

PMID: 33129938

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Project description:Antibody-mediated rejection (AbMR) adversely affects long-term graft survival in kidney transplantation. Currently, the diagnosis of AbMR requires a kidney biopsy, and detection of complement C4d deposition in the allograft is one of the diagnostic criteria. Complement activation also generates several soluble fragments which could potentially provide non-invasive biomarkers of the process. Furthermore, microvesicles released into the plasma from injured cells can serve as biomarkers of vascular injury. To explore whether soluble complement fragments or complement fragments bound to endothelial microvesicles can be used to non-invasively detect AbMR, we developed an in vitro model in which human endothelial cells were exposed to anti-HLA antibodies and complement sufficient serum. We found that complement fragments C4a and sC5b-9 were increased in the supernatants of cells exposed to complement-sufficient serum compared to cells treated complement-deficient serum. Furthermore, complement activation on the cell surface was associated with the release of microvesicles bearing C4 and C3 fragments. We next measured these analytes in plasma from kidney transplant recipients with biopsy-proven acute AbMR (n = 9) and compared the results with those from transplant recipients who also had impaired allograft function but who did not have AbMR (n = 30). Consistent with the in vitro results, complement fragments C4a and Ba were increased in plasma from patients with AbMR compared to control subjects (P < 0.001 and P < 0.01, respectively). Endothelial microvesicle counts were not increased in patients with AbMR, however, and the number of microvesicles with C4 and C3 bound to the surface was actually lower compared to control subjects (both P < 0.05). Our results suggest that plasma complement activation fragments may be useful as non-invasive biomarkers of antibody-mediated complement activation within the allograft. Complement-opsonized endothelial microvesicles are decreased in patients with AbMR, possibly due to enhanced clearance of microvesicles opsonized with C3 and C4 fragments.

Dataset Information

Live long and active: Polypeptide-mediated assembly of antibody variable fragments.

Publications

Live long and active: Polypeptide-mediated assembly of antibody variable fragments.

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