With great power, comes great responsibility: the importance of broadly measuring Fc-mediated effector function early in the antibody development process

mAbs, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 16, 2025

The field of antibody therapeutics is rapidly growing, with over 210 antibodies currently approved or in regulatory review and ~ 1,250 clinical development. Antibodies are highly versatile molecules that, strategic design their antigen-binding domain (Fab) the responsible for mediating effector functions (Fc), can be used a wide range therapeutic indications. Building on many years progress, biopharmaceutical industry now advancing innovative research development by exploring new targets formats using engineering to fine-tune tailored specific disease requirements. In addition considering target context, however, unique features each trigger diverse set Fc-mediated functions. To avoid unexpected results safety efficacy outcomes during later stages process, it crucial measure impact function early process. Given breadth deploy close interplay between Fab Fc functional domains, important conduct comprehensive evaluation an array antigen-specific biophysical cell-mediated assays. Here, we receptor properties that influence discuss implications safe efficacious therapeutics.

Language: Английский

---

A broad and potent neutralization epitope in SARS-related coronaviruses

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(29)

Published: June 29, 2022

Many neutralizing antibodies (nAbs) elicited to ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through natural infection and vaccination have reduced effectiveness SARS-CoV-2 variants. Here, we show that therapeutic antibody ADG20 is able neutralize variants of concern (VOCs) including Omicron (B.1.1.529) as well other SARS-related coronaviruses. We delineate the structural basis this relatively escape-resistant epitope extends from one end receptor binding site (RBS) into highly conserved CR3022 site. can then benefit high potency direct competition with ACE2 in more variable RBS interaction Importantly, are target generally a broad range VOCs, albeit against Omicron. Thus, vulnerable be exploited for design universal vaccines antibodies.

Language: Английский

---

Trends in industrialization of biotherapeutics: a survey of product characteristics of 89 antibody-based biotherapeutics

mAbs, Journal Year: 2023, Volume and Issue: 15(1)

Published: March 30, 2023

There is considerable interest in the pharmaceutical industry toward development of antibody-based biotherapeutics because they can selectively bind diverse receptors and often possess desirable pharmacology. Here, we studied product characteristics 89 marketed that were approved from 1986 to mid-2020 by gathering publicly available information. Our analyses revealed major trends their emergence as best-selling class pharmaceuticals. Early on, most therapeutic monoclonal antibodies developed treat cancer, with CD20 being common target. Thanks industrialization antibody manufacturing technologies, use has now blossomed include 15 different areas nearly 60 targets, field still growing! Drug manufacturers are solidifying choices regarding types molecular formats. IgG1 kappa continues be format among biotherapeutics. Most since 2015 either humanized or fully human, but data collected do not show a direct correlation between humanness reported incidence anti-drug antibodies. Furthermore, there have also been improvements terms drug stability high concentration liquid formulations suitable for subcutaneous route administration, which more recent years. These improvements, however, uniformly adopted across all areas, suggesting multiple options used serve purposes. Insights gained this analysis may help us devise better end-to-end biotherapeutic discovery strategies.

Language: Английский

---

Next-generation treatments: Immunotherapy and advanced therapies for COVID-19

Heliyon, Journal Year: 2024, Volume and Issue: 10(5), P. e26423 - e26423

Published: Feb. 19, 2024

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in 2019 following prior outbreaks of coronaviruses like SARS and MERS recent decades, underscoring their high potential infectivity humans. Insights from previous have played a significant role developing effective strategies to mitigate the global impact SARS-CoV-2. As January 7, 2024, there been 774,075,242 confirmed cases worldwide. To date, 13.59 billion vaccine doses administered, 7,012,986 documented fatalities (https://www.who.int/)Despite progress addressing rapid evolution SARS-CoV-2 challenges human defenses, presenting ongoing challenges. emergence new lineages, shaped mutation recombination processes, has led successive waves infections. This scenario reveals need for next-generation vaccines as crucial requirement ensuring protection against demand calls formulations that trigger robust adaptive immune response without leading inflammation linked with infection.Key mutations detected Spike protein, critical target neutralizing antibodies design —specifically within Receptor Binding Domain region Omicron variant lineages (B.1.1.529), currently dominant worldwide, intensified concerns due association immunity evasion vaccinations infections.As world deals this evolving threat, narrative extends realm emerging variants, each displaying implications remain largely misunderstood. Notably, JN.1 lineage is gaining prevalence, early findings suggest it stands among immune-evading characteristic attributed its L455S. Moreover, detrimental consequences novel bear particularly on immunocompromised individuals older adults. Immunocompromised face such suboptimal responses vaccines, rendering them more susceptible disease. Similarly, adults an increased risk disease presence comorbid conditions, find themselves at heightened vulnerability develop Thus, recognizing these intricate factors effectively tailoring public health protect vulnerable populations. In context, review aims describe, analyze, discuss current treatments encompassing immunotherapeutic approaches advanced therapies complements will offer solutions counter disadvantages existing options. Preliminary outcomes show virus address immunomodulatory associated COVID-19. Furthermore, capacity promote tissue repair demonstrated, which can be noteworthy who stand actors landscape possess broader potential, offering wide range variants enhancing ability constant virus. are projected treatment alternatives managing Chronic Post-COVID-19 syndromeand long-term complications.

Language: Английский

---

Breakthrough infection elicits hypermutated IGHV3-53/3-66 public antibodies with broad and potent neutralizing activity against SARS-CoV-2 variants including the emerging EG.5 lineages

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(12), P. e1011856 - e1011856

Published: Dec. 4, 2023

The rapid emergence of SARS-CoV-2 variants concern (VOCs) calls for efforts to study broadly neutralizing antibodies elicited by infection or vaccination so as inform the development vaccines and antibody therapeutics with broad protection. Here, we identified two convalescents breakthrough relatively high titers against all tested viruses. Among 50 spike-specific monoclonal (mAbs) cloned from their B cells, top 6 mAbs (KXD01-06) belong previously defined IGHV3-53/3-66 public antibodies. Although most in this class are dramatically escaped VOCs, KXD01-06 exhibit capacity, particularly KXD01-03, which neutralize prototype emerging EG.5.1 FL.1.5.1. Deep mutational scanning reveals that can be current prospective mutations on D420, Y421, L455, F456, N460, A475 N487. Genetic functional analysis further indicates extent somatic hypermutation is critical breadth other Overall, prevalence these provides rationale novel based Meanwhile, developed candidates through affinity maturation.

Language: Английский

---

Probing the biophysical constraints of SARS-CoV-2 spike N-terminal domain using deep mutational scanning

Science Advances, Journal Year: 2022, Volume and Issue: 8(47)

Published: Nov. 23, 2022

Increasing the expression level of SARS-CoV-2 spike (S) protein has been critical for COVID-19 vaccine development. While previous efforts largely focused on engineering receptor-binding domain (RBD) and S2 subunit, amino-terminal (NTD) long overlooked because limited understanding its biophysical constraints. In this study, effects thousands NTD single mutations S were quantified by deep mutational scanning. Our results revealed that in terms expression, tolerability residues was inversely correlated with their proximity to RBD S2. We also identified at interdomain interface increased without altering antigenicity. Overall, study not only advances constraints but provides invaluable insights into S-based immunogen design.

Language: Английский

---

Post-exposure prophylaxis with SA58 (anti-SARS-COV-2 monoclonal antibody) nasal spray for the prevention of symptomatic COVID-19 in healthy adult workers: a randomized, single-blind, placebo-controlled clinical study*

Emerging Microbes & Infections, Journal Year: 2023, Volume and Issue: 12(1)

Published: May 9, 2023

Monoclonal antibodies (mAbs) and the post-exposure prophylaxis (PEP) with mAbs represent a very important public health strategy against coronavirus disease 2019 (COVID-19). This study has assessed new Anti-SARS-COV-2 mAb (SA58) Nasal Spray for PEP COVID-19 in healthy adults aged 18 years older within three days of exposure to SARS-CoV-2 infected individual. Recruited participants were randomized ratio 3:1 receive SA58 or placebo. Primary endpoints laboratory-confirmed symptomatic period. A total 1222 dosed (SA58,

Language: Английский

---

Insights into next generation sequencing guided antibody selection strategies

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Oct. 26, 2023

Therapeutic antibody discovery often relies on in-vitro display methods to identify lead candidates. Assessing selected output diversity traditionally involves random colony picking and Sanger sequencing, which has limitations. Next-generation sequencing (NGS) offers a cost-effective solution with increased read depth, allowing comprehensive understanding of diversity. Our study establishes NGS guidelines for drug discovery, demonstrating its advantages in expanding the number unique HCDR3 clusters, broadening high affinity antibodies, total antibodies recognizing different epitopes, improving prioritization. Surprisingly, our investigation into correlation between NGS-derived frequencies CDRs revealed lack association, although this limitation could be moderately mitigated by leveraging clustering, enrichment and/or relative abundance across regions enhance This highlights benefits, offering insights, recommendations, most effective approach leverage therapeutic discovery.

Language: Английский

---

The Landscape of Neutralizing Monoclonal Antibodies (nAbs) for Treatment and Prevention of COVID-19

Journal of Pharmaceutical Innovation, Journal Year: 2023, Volume and Issue: 18(3), P. 1194 - 1212

Published: Feb. 20, 2023

Abstract Purpose After nearly 3 years of the COVID-19 pandemic, even though a vast body knowledge and products (including vaccines treatments) have been developed disseminated, virus is still evolving new variants arising. Consequently, thousands lives continue to be lost. Neutralizing monoclonal antibodies (nAbs) are promising drugs that emerged treat SARS-CoV-2. In uncertainty current situation, there question whether organizations should invest in this technology. To help decision-making scientifical pharmaceutical organizations, it major importance monitor development technologies. Therefore, aim study analyze landscape nAbs for COVID-19. Methods The scenario 473 biotherapeutics focusing on was evaluated using foresight techniques review literature. Data were obtained from structured semi-structured databases processed treatment, cleaning, consistency, validation, enrichment. Results We identified 227 performed an extensive literature 16 late clinical development, including technologies, responses concern (VOCs), manufacturing, aspects. Conclusions Even emergence VOCs threat effectiveness demanding constant genomic surveillance, use prevent will probably relevant due excellent safety profiles possibility immediate immunity transfer, especially patients showing inadequate immunological response vaccination. we suggest keep investing improvements

Language: Английский

---

Considerations for the development of monoclonal antibodies to address new viral variants in COVID-19

Expert Opinion on Biological Therapy, Journal Year: 2024, Volume and Issue: 24(8), P. 787 - 797

Published: Aug. 1, 2024

Monoclonal antibody (mAb) therapies proved safe and effective in preventing progression of COVID-19 to hospitalization, but most were eventually defeated by continued viral evolution. mAb combinations those mAbs that deliberatively selected target conserved regions the SARS-CoV-2 spike protein more resilient escape variants as evident longer clinical useful lives.

Language: Английский

---