Shark IgNAR-derived binding domains as potential diagnostic and therapeutic agents

Matz, Hanover; Dooley, Helen

doi:10.1016/j.dci.2018.09.007

Cited by 40 publications

(35 citation statements)

References 72 publications

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“…194 Besides camelids, cartilaginous fishes produce a distinct type of heavy-chain antibody containing a single variable region, V NAR , which could also serve as a therapeutic sdAb. 195 Similar to scFvs, sdAbs are amenable to tandem multimerization. Fusion of the same nanobody allows for increased valency and decreased antigen-dissociation rate, while fusion to distinct nanobodies allows for bispecific mechanisms to be explored.…”

Section: Single-domain Antibodiesmentioning

confidence: 99%

Considerations for the Design of Antibody-Based Therapeutics

Goulet

Atkins

2020

Journal of Pharmaceutical Sciences

161

154

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Keywords: antibody(s) antibody drug(s) antibody drug conjugate(s) (ADC) physicochemical properties pharmacokinetics monoclonal antibody(s) immunotherapy IgG antibody(s) drug design developability a b s t r a c t Antibody-based proteins have become an important class of biologic therapeutics, due in large part to the stability, specificity, and adaptability of the antibody framework. Indeed, antibodies not only have the inherent ability to bind both antigens and endogenous immune receptors but also have proven extremely amenable to protein engineering. Thus, several derivatives of the monoclonal antibody format, including bispecific antibodies, antibody-drug conjugates, and antibody fragments, have demonstrated efficacy for treating human disease, particularly in the fields of immunology and oncology. Reviewed here are considerations for the design of antibody-based therapeutics, including immunological context, therapeutic mechanisms, and engineering strategies. First, characteristics of antibodies are introduced, with emphasis on structural domains, functionally important receptors, isotypic and allotypic differences, and modifications such as glycosylation. Then, aspects of therapeutic antibody design are discussed, including identification of antigen-specific variable regions, choice of expression system, use of multispecific formats, and design of antibody derivatives based on fragmentation, oligomerization, or conjugation to other functional moieties. Finally, strategies to enhance antibody function through protein engineering are reviewed while highlighting the impact of fundamental biophysical properties on protein developability.

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Section: Single-domain Antibodiesmentioning

confidence: 99%

Considerations for the Design of Antibody-Based Therapeutics

Goulet

Atkins

2020

Journal of Pharmaceutical Sciences

161

154

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“…37 The identification of naturally occurring antibodies with paratopes containing extended CDR loops capable of protruding into the active site cleft is therefore correspondingly rare, but not unprecedented. [38][39][40] Overall, our analysis of the major conformational changes induced in ARG2 by inhibitory antibody binding support an innovative allosteric mechanism of inhibition. The combined effects of the Arg39 and Asn158 movement on removing the ability of His160 to act as a proton donor in catalysis, together with preventing the binding of substrate in a catalytically competent position, provide a detailed molecular understanding of the complete inhibition of ARG2 activity achieved by the antibodies.…”

Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Structural and functional characterization of C0021158, a high-affinity monoclonal antibody that inhibits Arginase 2 function via a novel non-competitive mechanism of action

Austin

Burschowsky

Chan

et al. 2020

mAbs

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Arginase 2 (ARG2) is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-arginine. The dysregulated expression of ARG2 within specific tumor microenvironments generates an immunosuppressive niche that effectively renders the tumor 'invisible' to the host's immune system. Increased ARG2 expression leads to a concomitant depletion of local L-arginine levels, which in turn leads to suppression of anti-tumor T-cell-mediated immune responses. Here we describe the isolation and characterization of a high affinity antibody (C0021158) that inhibits ARG2 enzymatic function completely, effectively restoring T-cell proliferation in vitro. Enzyme kinetic studies confirmed that C0021158 exhibits a noncompetitive mechanism of action, inhibiting ARG2 independently of L-arginine concentrations. To elucidate C0021158's inhibitory mechanism at a structural level, the co-crystal structure of the Fab in complex with trimeric ARG2 was solved. C0021158's epitope was consequently mapped to an area some distance from the enzyme's substrate binding cleft, indicating an allosteric mechanism was being employed. Following C0021158 binding, distinct regions of ARG2 undergo major conformational changes. Notably, the backbone structure of a surface-exposed loop is completely rearranged, leading to the formation of a new short helix structure at the Fab-ARG2 interface. Moreover, this large-scale structural remodeling at ARG2's epitope translates into more subtle changes within the enzyme's active site. An arginine residue at position 39 is reoriented inwards, sterically impeding the binding of L-arginine. Arg39 is also predicted to alter the pK A of a key catalytic histidine residue at position 160, further attenuating ARG2's enzymatic function. In silico molecular docking simulations predict that L-arginine is unable to bind effectively when antibody is bound, a prediction supported by isothermal calorimetry experiments using an L-arginine mimetic. Specifically, targeting ARG2 in the tumor microenvironment through the application of C0021158, potentially in combination with standard chemotherapy regimens or alternate immunotherapies, represents a potential new strategy to target immune cold tumors.

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“…Their significantly smaller size carries the advantage of diminishing steric hindrance that might prevent larger antibodies from accessing and recognizing certain epitopes [77] and, consequently, reducing their potential utility in disease therapy. In addition to the ability to circumvent complications related to accessibility, elasmobranch nanobodies have favorable attributes such as high affinity and antigen specificity, extraordinary thermal stability and resistance to denaturation, and the potential to complement classical antibodies [78]. Combined with the propensity to bind epitopes that are considered inaccessible to conventional monoclonal antibodies and their ability to resist denaturation, VNARs represent an emerging prospect for use in therapeutic, diagnostic, and biotechnological applications [78].…”

Section: Shark Antibody-derived Drug Delivery Systemsmentioning

confidence: 99%

“…Much remains to be understood about the role of IgNAR in the immune system of cartilaginous fishes. It is obvious, however, that the unique singular molecular framework of VNARs holds many advantages in developing reagents for scientific research, disease diagnosis, and potentially therapeutic interventions [78]. The large evolutionary distance between sharks and mammals facilitates successful IgNAR responses against antigen targets that are refractory to conventional methods of generating polyclonal and monoclonal antibodies.…”

Section: Shark Antibody-derived Drug Delivery Systemsmentioning

confidence: 99%

Potential Human Health Applications from Marine Biomedical Research with Elasmobranch Fishes

Luer

Walsh

2018

Fishes

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Members of the subclass of fishes collectively known as elasmobranchs (Class Chondrichthyes, Subclass Elasmobranchii) include sharks, skates, rays, guitarfish, and sawfish. Having diverged from the main line of vertebrate evolution some 400 million years ago, these fishes have continued to be successful in our ever-changing oceans. Much of their success must be attributed to their uncanny ability to remain healthy. Based on decades of basic research, some of their secrets may be very close to benefitting man. In this short review, some of the molecular and cellular biological areas that show promise for potential human applications are presented. With a brief background and current status of relevant research, these topics include development of new antibiotics and novel treatments for cancer, macular degeneration, viral pathogens, and Parkinson’s disease; potentially useful genomic information from shark transcriptomes; shark antibody-derived drug delivery systems; and immune cell-derived compounds as potential cancer therapeutic agents.

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Shark IgNAR-derived binding domains as potential diagnostic and therapeutic agents

Cited by 40 publications

References 72 publications

Considerations for the Design of Antibody-Based Therapeutics

Considerations for the Design of Antibody-Based Therapeutics

Structural and functional characterization of C0021158, a high-affinity monoclonal antibody that inhibits Arginase 2 function via a novel non-competitive mechanism of action

Potential Human Health Applications from Marine Biomedical Research with Elasmobranch Fishes

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