bird-flu-stocks-logo
birdflustocks.com
Antibodies
birdflustocks.com » Facts » Medical Countermeasures  » Antibodies
If minor or no immunity exists in the bulk of the human population, as with the 1918 Spanish flu, new pandemics can arise. Thus, the emergence of new influenza strains and lack of herd immunity in the population remains a persistent threat to human health.
Given the sporadic occurrence of oseltamivir-resistant viruses, the characterization of zanamivir-resistant viruses and the lack of heterovariant vaccines, alternative treatment strategies for influenza are urgently needed. Immunotherapy with monoclonal antibodies represents a complementary strategy to current antivirals. The use of monoclonal antibodies for treatment of medical conditions, including viral diseases like hepatitis and respiratory syncytial virus, is well established.
Monoclonal antibody therapy could be employed alone for the treatment of influenza infections with strains that are resistant to current antivirals or in combination with antivirals in the case of terminal patients with severe influenza infections. Prophylactic administration of antibodies could be valuable in the case of a pandemic with a highly pathogenic virus like H5N1 especially for persons which are particular susceptible to illness like elderly and immunocompromised individuals, and people with a higher risk of getting infections as health-related and hospital workers.
Source: Broadly neutralizing antibodies against influenza viruses
Cross protection against infectious diseases is extremely important due to the existence of multiple virus subtypes. Vaccines have successfully eradicated smallpox and can control other viral infections. However, not all current vaccines are universal. For example, seasonal viruses such as influenza spread around the world because antigenic drift and antigenic shift, mainly of membrane proteins such as hemagglutinin (HA), permit the virus to escape host immunity. There are fewer therapeutic monoclonal antibodies (mAbs) against viral infections than there are against cancer and autoimmune disease, mainly because viral antigens are continuously evolving. Therefore, the development of a universal vaccine or broadly neutralizing mAbs (bnAbs) is important to assist with the control of viral infections.
Here, we review how cross-protection can be achieved, via passive immunotherapy or vaccination, against influenza, a representative viral infection. Recently, several bnAbs against the influenza virus that produce cross-protection have been isolated.
Source: Broadly Neutralizing Antibodies for Influenza: Passive Immunotherapy and Intranasal Vaccination

SAB Biotherapeutics: SAB-176

SAB-176 is being developed for several influenza indications, including treatment of high-risk patient populations, as well as pre- and post-exposure prophylaxis. The FDA’s Breakthrough Therapy designation confirms that the multi-epitope targeting modality of SAB-176 has a clear differentiation vs. monoclonal antibodies (mAb) that bind to a single epitope, and SAB’s treatment can sustain its efficacy over viral mutations and prevent or reduce the risk of emerging treatment-resistant influenza strains. Virus evolution driven by vaccines or treatments is a serious challenge and the use of therapeutics can create “escape mutants” or versions of a virus that have changed to escape pressure on virus survival driven by an antiviral treatment, whether it is a small molecule or monoclonal antibody modality.
SAB’s polyclonal antibodies exhibit broad neutralization across multiple epitopes of Influenza A and B viruses. SAB-176 has a half-life that allows long-term protection against a virus and its mutations with a single dose. These fully human antibodies can neutralize many different variants of influenza A and B. SAB-176’s recently completed clinical proof-of-concept Phase 2A trial showed statistically significant reduction in viral load, confirming high cross-reactivity (the ability to recognize and react to strains it was not specifically produced against) to the pandemic influenza strain (not targeted with immunogen to produce SAB-176 treatment) in humans. SAB’s fully human polyclonal antibodies achieved both statistically significant reduction in viral load and statistically significant improvement in symptomology at Day 4, confirming SAB-176’s favorable safety and tolerability profile.

SAB-176 has now received both Breakthrough and Fast Track designations from FDA – signifying its potential to fundamentally improve influenza treatment and prophylaxis
Source: SAB Biotherapeutics Announces U.S. FDA Grants Breakthrough Therapy Designation to SAB-176 Influenza Immunotherapy
SAB Biotherapeutics (...) today announced that the Navy Medical Research Command (NMRC) is moving forward with a safety and tolerability study to evaluate SAB-176, a therapy being investigated for use as a pre- and post-exposure prophylactic treatment for influenza type A and type B, pursuant to the Cooperative Research and Development Agreement that governs the relationship between SAB and the NMRC.
With funding for research provided by the Henry Jackson Foundation, this partnership will move forward a pharmacokinetic (PK), safety and tolerability study designed as a double-blinded, randomized study with intramuscular SAB-176 administered to healthy volunteers. The NMRC Clinical Trials Center, located in Bethesda, Maryland, will be conducting this PK study under the leadership of Cmdr. Nehkonti Adams, Director, NMRC Clinical Trials Center.
SAB has utilized its proprietary DiversitAb™ platform to manufacture SAB-176, fully human polyclonal antibodies targeting influenza from Transchromosomic (Tc) Bovine™. SAB-176 is a novel multi-target biologic that has shown sustained neutralization activity across multiple virus strains of Influenza A and B. In 2023, the U.S. Food and Drug Administration granted Breakthrough Therapy and Fast Track Designations to SAB-176 based on the results of the completed clinical proof-of-concept Phase 2 study in an influenza challenge model with intravenous (IV) formulation. SAB-176, along with several other fully human anti-infective immunoglobulins developed by SAB have been administered through IV to over 700 healthy volunteers and patients. This will be the first study to examine intramuscular administration of any DiversitAb™ platform product. The DiversitAb™ platform produces fully human target-specific biologics that can be delivered across a range of therapeutic areas, including infectious diseases and autoimmune conditions like type 1 diabetes (T1D).
SAB Chairman and CEO Samuel J. Reich stated that “we are pleased to continue our collaboration with the NMRC to explore new routes of administration for our products. (...)
Source: SAB Biotherapeutics Announces Clinical Partnership with Naval Medical Research Center to Advance Potential Influenza Treatment

Cidara Therapeutics: CD388

Cidara is developing a new generation of immunotherapeutic agents from its Cloudbreak platform that couple potent drugs to a human antibody fragment. These highly potent, long-acting drug-Fc conjugates (DFCs) are designed to inhibit specific disease targets while simultaneously engaging the immune system.
Cidara is developing CD388, a flu DFC, to achieve universal prevention of seasonal and pandemic influenza with a single dose. DFCs are not vaccines or monoclonal antibodies. Their targeting domains are small molecule antivirals that bind to a highly conserved target on the influenza cell surface, which is essential for viral proliferation and enables universal influenza coverage. These long-acting, bispecific DFCs are designed to directly inhibit viral proliferation while simultaneously directing immune-mediated clearance of the virus. The two distinct and complementary mechanisms are designed to maximize antiviral activity of DFCs.
Flu DFCs have the potential to offer significant advantages over current flu vaccines:
- True universal protection, against all influenza strains and for all people, including those with a compromised immune system
- Near-immediate protective effects
Mouse study

U.S. Food and Drug Administration (FDA) has granted Fast Track designation to CD388, Cidara’s novel drug-Fc conjugate (DFC) candidate. CD388 is being developed in collaboration with Janssen Pharmaceuticals for the prevention of influenza A and B infection (...) Cidara recently announced promising interim efficacy and safety data from the ongoing Phase 2a study, being conducted in collaboration with Janssen Pharmaceuticals, Inc. (Janssen), one of the Janssen Pharmaceutical Companies of Johnson & Johnson, that is evaluating the pre-exposure prophylactic activity of CD388 against the H3N2 influenza A virus strain.
Source: Cidara Therapeutics Receives U.S. FDA Fast Track Designation for CD388, a Novel Drug-Fc Conjugate Targeting Influenza A and B
Cidara Therapeutics (...) today announced that it has entered into a definitive agreement with Johnson & Johnson to reacquire the exclusive global development and commercial rights to CD388, which is in development for the prevention of all strains of influenza A and B.
Concurrent with the acquisition, Cidara closed a definitive agreement for the sale of preferred stock in a private placement led by RA Capital Management, with significant participation from Bain Capital Life Sciences, Biotech Value Fund (BVF), and Canaan Partners. The private placement provides $240 million in gross proceeds that will be used by Cidara to develop CD388 as a universal preventative against seasonal and pandemic influenza A and B, beginning with a Phase 2b clinical trial in the upcoming Northern Hemisphere influenza season. The proceeds from the private placement fund the upfront payment under the agreement with Johnson & Johnson and are expected to provide runway beyond topline data from CD388’s Phase 2b trial. (...)
Dr. Stein continued, “This reacquisition of CD388, along with the capital to advance it through Phase 2b development, is transformational for Cidara and especially for those who could benefit from a long-acting, universal preventative against all forms of influenza. In our Phase 2b study later this year, we will evaluate the efficacy and safety of CD388 in providing season-long, universal protection from influenza. We believe that CD388 may have significant advantages beyond and in addition to flu vaccines, with the potential for universal protection even in the absence of a robust immune response and without the requirement for seasonal influenza strain prediction.”
All responsibility for future development, manufacturing, and commercialization activities of CD388 will be assumed by Cidara. In exchange for reacquiring the exclusive global development and commercial rights to CD388, Johnson & Johnson has received from Cidara a one-time upfront payment of $85 million and is eligible to receive potential additional development, regulatory, and commercial milestone payments.
Source: Cidara Therapeutics Reacquires Global Development and Commercial Rights to CD388 and Announces Private Placement Financing of $240 Million

Vir Biotechnology: VIR-2482

A phase 2 study of VIR-2482 ended unsuccessfully. The final results have been published in April 2024 and can be found here.
VIR-2482 is an investigational intramuscularly administered influenza A-neutralizing monoclonal antibody. In vitro, it has been shown to cover all major strains of influenza A that have arisen since the 1918 Spanish flu pandemic. VIR-2482 is designed as a universal prophylactic for influenza A. It has the potential to overcome the limitations of current flu vaccines and lead to meaningfully higher levels of protection due to its broad strain coverage and because it does not rely on an individual to create their own protective antibody response. VIR-2482, which incorporates Xencor’s Xtend™ Technology, also has been half-life engineered so a single dose has the potential to last the entire flu season. Under the collaboration agreement signed with GlaxoSmithKline (GSK) in 2021, GSK has an exclusive option to lead post-Phase 2 development and commercialization of VIR-2482.

Vir Biotechnology, Inc. (Nasdaq: VIR) today announced that the Phase 2 (...) trial evaluating VIR-2482 for the prevention of symptomatic influenza A illness did not meet primary or secondary efficacy endpoints. In participants who received the highest dose of VIR-2482 (1,200 mg), a non-statistically significant reduction of approximately 16% in influenza A protocol-defined illness was observed. Participants who received the highest dose showed an approximately 57% reduction in symptomatic influenza A illness, when defined according to CDC influenza-like-illness criteria, which was one of two secondary endpoints. VIR-2482 was generally well tolerated and no safety signals were identified.
Source: Vir Biotechnology Announces Topline Data from Phase 2 PENINSULA Trial Evaluating VIR-2482 for the Prevention of Seasonal Influenza A Illness

Vir Biotechnology: VIR-2981

VIR-2981 is in a pre-clinical stage. While there is no press release with further information, the pipeline section on their website indicates a collaboration with GSK, maybe under similar conditions as the VIR-2482 development.
VIR-2981 is an investigational neuraminidase-targeting monoclonal antibody against influenza viruses. It targets a region of the neuraminidase protein that is highly conserved across influenza A and B strains and is designed to inhibit the influenza neuraminidase, a key viral protein that facilitates release of new viruses in infected individuals. Preclinical data demonstrate the antibody’s breadth and potency against all major strains of seasonal and pandemic influenza viruses and support the potential of this antibody in the prevention of influenza illness.

In the meantime, we are continuing to advance next generation solutions for serious respiratory infections, including VIR-2981, an investigational neuraminidase-targeting monoclonal antibody against both influenza A and B viruses.
Source: Vir Biotechnology Announces Topline Data from Phase 2 PENINSULA Trial Evaluating VIR-2482 for the Prevention of Seasonal Influenza A Illness

Johnson & Johnson / Leyden Laboratories: CR9114

CR9114 is in a pre-clinical stage. It has been developed by Johnson & Johnson and was licensed to Leyden Laboratories to develop a nasal spray. CR9114 has shown promising results against a broad range of influenza strains including H5N1. Intranasal administration fully protected mice from H5N1 infections a low viral doses.

Avian A(H5N1) influenza virus poses an elevated zoonotic threat to humans, and no pharmacological products are currently registered for fast-acting pre-exposure protection in case of spillover leading to a pandemic. Here, we show that an epitope on the stem domain of H5 hemagglutinin is highly conserved and that the human monoclonal antibody CR9114, targeting that epitope, potently neutralizes all pseudotyped H5 viruses tested, even in the rare case of substitutions in its epitope. Further, intranasal administration of CR9114 fully protects mice against A(H5N1) infection at low dosages, irrespective of pre-existing immunity conferred by the quadrivalent seasonal influenza vaccine. These data provide a proof-of-concept for broad, pre-exposure protection against a potential future pandemic using the intranasal administration route.
Source: A pan-influenza monoclonal antibody neutralizes H5 strains and prophylactically protects through intranasal administration
Prophylactic monoclonal antibodies could prevent community spread in the period before and during vaccination campaigns, but pre-exposure administration of anti-influenza antibodies through the systemic route has failed in human trials, with VIR-2482 as latest example. Currently, it is unknown whether passive immunization with antibodies delivered into the nasal cavity, at the port of entry for influenza virus, could slow down a pandemic in the period before and during vaccine roll-out.
Source: A pan-influenza monoclonal antibody neutralizes H5 strains and prophylactically protects through intranasal administration
Leyden Laboratories B.V. (the “Company” or “Leyden Labs”), today announces the development of an intranasal spray protecting against influenza A and influenza B based on the human monoclonal antibody CR9114. Leyden Labs has entered into an exclusive licensing agreement with Janssen Pharmaceuticals, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, to develop and commercialize CR9114 for mucosal administration. CR9114 is a human monoclonal antibody that protects against both influenza A and B in preclinical models. With the exclusive license to mucosal administration of CR9114, Leyden Labs is developing easy-to-use products that provide immediate protection against contracting and spreading multiple strains of influenza. This supports Leyden Labs’ mission to optimize mucosal protection against entire viral families to prevent future pandemics. Under the terms of the licensing agreement, Janssen will provide Leyden Labs with a worldwide, exclusive license to develop and commercialize CR9114 for mucosal administration. Janssen will receive an upfront payment and is eligible to receive development and sales-based milestone payments and tiered royalties on potential sales. The agreement was facilitated by Johnson & Johnson Innovation.
Source: Leyden Labs Licenses Pan-Influenza Antibody from Janssen
Even within the realm of HA-stem reactive hmAbs, universal protection is rare. For instance, the hmAbs 2G02 (27) and FI6 (28) are highly cross-reactive but fail to interact with B HAs. The broadest HA-stem reactive hmAb is the VH1-69 antibody CR9114 (29): prophylactic systemic administration of CR9114 fully protects mice from mortality and weight loss when challenged with influenza A1, A2, B/Yamagata, and B/Victoria strains (29–31) (Figure 1A). CR9114 was recovered from a combinatorial display library constructed from human B cells of healthy recently vaccinated volunteers. CR9114 neutralizes in vitro most influenza viruses except for some H2N2 and H7, and influenza B strains. Although these are not neutralized in vitro by CR9114, the hmAb still protects mice from lethal challenge with these viruses. This demonstrates that HA neutralization is not the only mechanism by which CR9114 protects against influenza. Microneutralization assays specifically detect whether antibodies prevent infection of mammalian cells by (pseudo)virions. Even though CR9114 does not neutralize some H2N2, some H7, or influenza B in vitro, it still protects in vivo. This shows that in vitro neutralization of HA is an imperfect correlate of protection, as it is not always a predictor of protection.
Source: The influenza hemagglutinin stem antibody CR9114: Evidence for a narrow evolutionary path towards universal protection

Johnson & Johnson / Scripps Research: MD3606

MD3606 is in a pre-clinical stage. It has been developed by Johnson & Johnson in cooperation with Scripps Research. The multidomain antibody MD2470 combines the four different variable domains SD36, SD38, SD83, and SD84. While MD2470 is derived from llamas, it is combined with a human Fc receptor and together they constitute MD3606.

We report the use of diverse camelid single-domain antibodies to influenza virus hemagglutinin to generate multidomain antibodies with impressive breadth and potency. Multidomain antibody MD3606 protects mice against influenza A and B infection when administered intravenously or expressed locally from a recombinant adeno-associated virus vector. Crystal and single-particle electron microscopy structures of these antibodies with hemagglutinins from influenza A and B viruses reveal binding to highly conserved epitopes. Collectively, our findings demonstrate that multidomain antibodies targeting multiple epitopes exhibit enhanced virus cross-reactivity and potency. In combination with adeno-associated virus–mediated gene delivery, they may provide an effective strategy to prevent infection with influenza virus and other highly variable pathogens.
Source: Universal protection against influenza infection by a multidomain antibody to influenza hemagglutinin
Immunologist James Crowe, an influenza antibody specialist and vaccine developer at Vanderbilt University in Nashville, cautions that human immune systems may see the llama-derived proteins as foreign and develop antibodies against them.
Source: Nasal gene spray inspired by llama antibodies could prevent all types of flu
All four VHHs were obtained by immunizing llamas with recombinant hemagglutinin (HA). VHH (SD38) can neutralize group 1 influenza A viruses and weakly neutralize some group 2 viruses, VHH (SD36) neutralizes group 2 influenza A viruses, and VHH (SD83 and SD84) neutralizes influenza B viruses. A tetravalent multidomain antibody (MDAb; MD2407) was generated by connecting VHHs with (GGGGS)2-linkers. An MDAb–Fc fusion (MD3606) was generated by attaching MD2407 to the human IgG Fc region. MD2407 and MD3606 neutralized influenza A and B viruses in vitro. Intranasal injection with an AAV vector encoding a humanized MD3606, administered 7 days before exposure, provided broad cross-protection against a lethal dose of H1N1, H3N2, and influenza B virus.
Source: Broadly Neutralizing Antibodies for Influenza: Passive Immunotherapy and Intranasal Vaccination
Passive immunization with multivalent MDAbs based on VHH could control circulating influenza virus. If we succeeded in generating multivalent MDAb with several VHHs against each influenza A virus (group 1 or group 2), or B virus, even one reagent would induce cross-protection for whole influenza subtypes. These strategies could help to prevent future influenza pandemics.
Source: Broadly Neutralizing Antibodies for Influenza: Passive Immunotherapy and Intranasal Vaccination
Laursen et al. (2018), propose a solution for the problem of targeting diverse epitopes in a single antibody construct. The authors generated a multidomain antibody construct that comprises 4 different single-domain antibodies that are genetically fused tail-to-head into a single recombinant biological that was expressed in and purified from Expi293F cells (Fig. 1A). The 4 single-domain antibodies are derived from camelid-heavy chain-only antibodies that can neutralize group 1 influenza A, group 2 influenza A, and influenza B viruses from the Yamagata and Victoria lineage, respectively (Laursen et al., 2018). Three of the single domain antibodies recognize the HA stalk while the fourth binds to the influenza B HA head and exhibited HI activity. Eventually, a very broadly protecting multidomain antibody construct was generated by genetically fusing the individual single domain antibodies tail-to-head to each other, each separated by a flexible linker. The tandem construct was then fused to a human IgG1 Fc domain (Fig. 1A). The resulting biological, named MD3606, could neutralize all influenza A and B viruses tested, including H1, H2, H3, H5, H7 and H9 subtype viruses (except for an H12 virus). Remarkably, the multidomain construct was more potent than each of the individual components, which could be explained by the possible crosslinking of 2 HA trimers on a virion or on the surface of infected cells by the dimeric multidomain molecule MD3606.
Source: New antibody-based prevention and treatment options for influenza

Johnson & Johnson: CR6261 and CR8020

CR6261 has failed a phase 2 study. There are no published results regarding CR8020 in recent years, so it has probably failed too. They have been developed by Crucell, which is now part of Johnson & Johnson. Nonetheless, their failure has provided valuable data to learn from.

We conducted a randomized, double-blind, phase 2, placebo-controlled trial of a monoclonal antibody that targets the HA stalk (CR6261) in a H1N1pdm09 healthy volunteer human challenge model. A single 50 mg/kg dose of CR6261 was infused 24 hours after challenge. The primary efficacy outcome was area under the curve (AUC) of viral RNA detection over time. (...) The results of this study suggest that a monoclonal anti-stalk approach to prevent or treat influenza infection may be limited in efficacy. Future approaches should consider including and evaluating anti-stalk antibodies as part of a multifaceted strategy rather than as a stand-alone therapeutic.
Source: Safety and Efficacy of CR6261 in an Influenza A H1N1 Healthy Human Challenge Model

Universal Influenza Vaccine Technology Landscape

A great vaccine database with a different focus is the Universal Influenza Vaccine Technology Landscape by CIDRAP.