The state-of-play and future of antibody therapeutics

Elgundi, Zehra; Reslan, Mouhamad; Cruz, Esteban; Sifniotis, Vicki; Kayser, Veysel

doi:10.1016/j.addr.2016.11.004

Cited by 256 publications

(199 citation statements)

References 208 publications

Supporting

Mentioning

190

Contrasting

Unclassified

Order By: Relevance

“…Among the products, most of them were developed to treat chronic inflammatory diseases and cancer, but there are also products in the market for neurodegenerative disorders and for infectious diseases (13). …”

Section: Monoclonal Antibodies (Mabs): From Biotechnological Assays Tmentioning

confidence: 99%

Camelid Single-Domain Antibodies As an Alternative to Overcome Challenges Related to the Prevention, Detection, and Control of Neglected Tropical Diseases

et al. 2017

View full text Add to dashboard Cite

Due mainly to properties such as high affinity and antigen specificity, antibodies have become important tools for biomedical research, diagnosis, and treatment of several human diseases. When the objective is to administer them for therapy, strategies are used to reduce the heterologous protein immunogenicity and to improve pharmacokinetic and pharmacodynamic characteristics. Size minimization contributes to ameliorate these characteristics, while preserving the antigen–antibody interaction site. Since the discovery that camelids produce functional antibodies devoid of light chains, studies have proposed the use of single domains for biosensors, monitoring and treatment of tumors, therapies for inflammatory and neurodegenerative diseases, drug delivery, or passive immunotherapy. Despite an expected increase in antibody and related products in the pharmaceutical market over the next years, few research initiatives are related to the development of alternatives for helping to manage neglected tropical diseases (NTDs). In this review, we summarize developments of camelid single-domain antibodies (VHH) in the field of NTDs. Particular attention is given to VHH-derived products, i.e., VHHs fused to nanoparticles, constructed for the development of rapid diagnostic kits; fused to oligomeric matrix proteins for viral neutralization; and conjugated with proteins for the treatment of human parasites. Moreover, paratransgenesis technology using VHHs is an interesting approach to control parasite development in vectors. With enormous biotechnological versatility, facility and low cost for heterologous production, and greater ability to recognize different epitopes, VHHs have appeared as an opportunity to overcome challenges related to the prevention, detection, and control of human diseases, especially NTDs.

show abstract

Section: Monoclonal Antibodies (Mabs): From Biotechnological Assays Tmentioning

confidence: 99%

Camelid Single-Domain Antibodies As an Alternative to Overcome Challenges Related to the Prevention, Detection, and Control of Neglected Tropical Diseases

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Since the approval of Orthoclone OTK3 in 1986, over 50 mAb‐based biologics have been launched, comprising half of the $140 billion biopharmaceutical market (Chiu & Gilliland, 2016; Elgundi, Reslan, Cruz, Sifniotis, & Kayser, 2017). The ability to generate high affinity candidates to a broad range of targets, together with the development of multi‐partite therapeutic strategies, has rendered mAbs and their derivatives important scaffolds (Aggarwal, 2014).…”

Section: Introductionmentioning

confidence: 99%

Using extensional flow to reveal diverse aggregation landscapes for three IgG1 molecules

Willis

Kumar

Dobson

et al. 2018

Biotech & Bioengineering

View full text Add to dashboard Cite

Monoclonal antibodies (mAbs) currently dominate the biopharmaceutical sector due to their potency and efficacy against a range of disease targets. These proteinaceous therapeutics are, however, susceptible to unfolding, mis‐folding, and aggregation by environmental perturbations. Aggregation thus poses an enormous challenge to biopharmaceutical development, production, formulation, and storage. Hydrodynamic forces have also been linked to aggregation, but the ability of different flow fields (e.g., shear and extensional flow) to trigger aggregation has remained unclear. To address this question, we previously developed a device that allows the degree of extensional flow to be controlled. Using this device we demonstrated that mAbs are particularly sensitive to the force exerted as a result of this flow‐field. Here, to investigate the utility of this device to bio‐process/biopharmaceutical development, we quantify the effects of the flow field and protein concentration on the aggregation of three mAbs. We show that the response surface of mAbs is distinct from that of bovine serum albumin (BSA) and also that mAbs of similar sequence display diverse sensitivity to hydrodynamic flow. Finally, we show that flow‐induced aggregation of each mAb is ameliorated by different buffers, opening up the possibility of using the device as a formulation tool. Perturbation of the native state by extensional flow may thus allow identification of aggregation‐resistant mAb candidates, their bio‐process parameters and formulation to be optimized earlier in the drug‐discovery pipeline using sub‐milligram quantities of material.

show abstract

“…In order to advance h2E2 toward clinical trials, it is necessary to establish a master cell bank to permit the production of protein suitable for use in humans [9]. The selection of a single clone is a critical step in establishing this cell bank [10]. It was shown, using the same material as in the current study, that post-translational modifications (glycosylation) can vary between h2E2 produced by different clones (cell lines) with different production yields [11].…”

Section: Introductionmentioning

confidence: 99%

Characterization of a recombinant humanized anti-cocaine monoclonal antibody produced from multiple clones for the selection of a master cell bank candidate

Wetzel

Webster

Saeed

et al. 2017

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

We have generated a humanized anti-cocaine monoclonal antibody (mAb), which is at an advanced stage of pre-clinical development. We report here in vitro binding affinity studies, and in vivo pharmacokinetic and efficacy studies of the recombinant mAb. The overall aim was to characterize the recombinant antibody from each of the three highest producing transfected clones and to select one to establish a master cell bank. In mAb pharmacokinetic studies, after injection with h2E2 (120 mg/kg iv) blood was collected from the tail tip of mice over 28 days. Antibody concentrations were quantified using ELISA. The h2E2 concentration as a function of time was fit using a two-compartment pharmacokinetic model. To test in vivo efficacy, mice were injected with h2E2 (120 mg/kg iv), then one hour later injected with an equimolar dose of cocaine. Blood and brain were collected 5 minutes after cocaine administration. Cocaine concentrations were quantified using LC/MS. The affinity of the antibody for cocaine was determined using a [3H] cocaine binding assay. All three antibodies had long elimination half-lives, 2–5 nM Kds for cocaine, and prevented cocaine’s entry into the brain by sequestering it in the plasma. Pharmacokinetic and radio-ligand binding assays supported designation of the highest producing clone (85) as the master cell bank candidate. Overall, the recombinant h2E2 showed favorable binding properties, pharmacokinetics, and in vivo efficacy.

show abstract

The state-of-play and future of antibody therapeutics

Cited by 256 publications

References 208 publications

Camelid Single-Domain Antibodies As an Alternative to Overcome Challenges Related to the Prevention, Detection, and Control of Neglected Tropical Diseases

Camelid Single-Domain Antibodies As an Alternative to Overcome Challenges Related to the Prevention, Detection, and Control of Neglected Tropical Diseases

Using extensional flow to reveal diverse aggregation landscapes for three IgG1 molecules

Characterization of a recombinant humanized anti-cocaine monoclonal antibody produced from multiple clones for the selection of a master cell bank candidate

Contact Info

Product

Resources

About