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COVID-19 Long-Acting AntiBody (LAAB) combination AZD7442 rapidly advances into Phase III clinical trials
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AstraZeneca started late-stage trials on Saturday older people and those in long-term care, as well as people with conditions such as cancer and HIV, will be recruited to take part in the Provent trial........[nov 20] of an experimental long-acting monoclonal antibody combination drug it hopes could be used as a so-called prophylactic to prevent COVID-19 infection in at-risk people for up to 12 months. The prophylactic treatment differs from a vaccine in that it introduces antibodies, rather than prompting the body's immune system to make them. It may prove useful in people whose immune systems are weaker or compromised, and who don't respond to vaccination. "What we are investigating in this study is whether we can provide protection by giving antibodies that have been shown to neutralise the virus, by injection into the muscle," Monoclonal antibodies mimic natural antibodies that the body generates to fight off infection. They can be synthesised in the laboratory and are already used to treat some types of cancer. AstraZeneca said its COVID-19 cocktail - which combines two monoclonal antibodies - has the potential both to treat and prevent disease progression in patients already infected with the SARS-CoV-2 virus, and to be given as a preventative medication prior to people such as healthcare workers being exposed to the virus. "These have been engineered specifically to have what we call a long half-life, (so) we think they will confer protection for (at least) six, but more likely closer to 12 months," Under a plan to set up a global production network, Astra in October enlisted contract manufacturer Lonza to produce the drug in Portsmouth, New Hampshire, starting in the first half of 2021.......British scientists from the University College London Hospitals NHS (UCLH) have already injected ten people with the drug as part of the new trial called Storm Chaser, with an aim to trial the new treatment on 1,125 people globally. The participants received two consecutive doses of the drug. Scientists from the UCLH have also begun a second clinical trial named Provent, to examine the use of the antibody for people who may not benefit from vaccines, such as patients with a compromised immune system, or those at increased risk of Covid-19 infection due to factors such as age and existing conditions.
Licensed from Vanderbilt University: This Spring, scientists at Vanderbilt University used the Berkeley Lights Platform to quickly identify lead molecules that bind and block the interaction of SARS-CoV-2 Spike protein with the human ACE-2 receptor. Two of these antibodies are part of the long-acting antibody (LAAB) combination, also known as AZD7442, which is now part of two of AstraZeneca's Phase III clinical trials (1).
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Phase III Double-blind, Placebo-controlled Study of AZD7442 for Post- Exposure Prophylaxis of COVID-19 in Adults (STORM CHASER)..https://clinicaltrials.gov/ct2/show/NCT04625972
AstraZeneca is developing mAbs to the SARS-CoV-2 S protein. The SARS-CoV-2 spike protein contains the virus's RBD, which enables the virus to bind to receptors on human cells. By targeting this region of the virus's spike protein, antibodies can block the virus's attachment to human cells, and, therefore, is expected to block infection. Amino acid substitutions have been introduced into the antibodies to both extend their half-lives, which should prolong their potential prophylactic benefit, and decrease Fc effector function in order to decrease the potential risk of antibody-dependent enhancement of disease. AZD7442, a combination of 2 of these mAbs (AZD8895 and AZD1061), is being evaluated for administration to prevent and/or treat COVID-19. There is currently one ongoing Phase I study with AZD7442.
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COVID-19 Long-Acting AntiBody (LAAB) combination AZD7442 rapidly advances into Phase III clinical trials - published
https://www.nature.com/articles/s41586-020-2548-6
Potently neutralizing and protective human antibodies against SARS-CoV-2
Nature July 2020
Abstract
The ongoing pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health1 and the medical countermeasures available so far are limited2,3. Moreover, we currently lack a thorough understanding of the mechanisms of humoral immunity to SARS-CoV-24. Here we analyse a large panel of human monoclonal antibodies that target the spike (S) glycoprotein5, and identify several that exhibit potent neutralizing activity and fully block the receptor-binding domain of the S protein (SRBD) from interacting with human angiotensin-converting enzyme 2 (ACE2). Using competition-binding, structural and functional studies, we show that the monoclonal antibodies can be clustered into classes that recognize distinct epitopes on the SRBD, as well as distinct conformational states of the S trimer. Two potently neutralizing monoclonal antibodies, COV2-2196 and COV2-2130, which recognize non-overlapping sites, bound simultaneously to the S protein and neutralized wild-type SARS-CoV-2 virus in a synergistic manner. In two mouse models of SARS-CoV-2 infection, passive transfer of COV2-2196, COV2-2130 or a combination of both of these antibodies protected mice from weight loss and reduced the viral burden and levels of inflammation in the lungs. In addition, passive transfer of either of two of the most potent ACE2-blocking monoclonal antibodies (COV2-2196 or COV2-2381) as monotherapy protected rhesus macaques from SARS-CoV-2 infection. These results identify protective epitopes on the SRBD and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutic agents.
These studies demonstrate that although a wide range of human neutralizing antibodies are elicited by natural infection with SARS-CoV-2, only a small subset of those monoclonal antibodies are of high potency (IC50 < 50 ng ml−1 against wild-type SARS-CoV-2 virus). Biochemical and structural analysis of these potent monoclonal antibodies defined three principal antigenic sites of vulnerability on the SRBD for SARS-CoV-2 neutralization. Representative monoclonal antibodies from two antigenic sites were shown to synergize in vitro and confer protection as an in vivo cocktail in both prophylactic and therapeutic treatment. Our findings reveal critical features of effective humoral immunity to SARS-CoV-2 and suggest that the role of synergistic neutralization activity in polyclonal responses should be investigated further. Moreover, as SARS-CoV-2 continues to circulate, population-level immunity elicited by natural infection may start to select for antigenic variants that escape the selective pressure of neutralizing antibodies. Other groups have reported the selection of SARS-CoV-2 RBD escape mutations in the presence of single monoclonal antibodies, but not in the presence of a mixture of two antibodies45, which reinforces the need to target multiple epitopes of the S protein in vaccines or immunotherapies. So far, the gene that encodes the S protein has been found to be limited in diversity-with the exception of a D614G substitution46, which is far away from the amino acid positions identified in our mutational studies for the antibodies we have considered here. Rationally selected therapeutic cocktails such as the one we describe are likely to offer greater resistance to SARS-CoV-2 escape than single antibodies. Our results provide a basis for the preclinical evaluation and development of the identified monoclonal antibodies as candidates for use as COVID-19 immunotherapeutic agents in humans.
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COVID-19 Long-Acting AntiBody (LAAB) combination AZD7442 rapidly advances into Phase III clinical trials
9 October 2020
https://www.astrazeneca.com/media-centre/press-releases/
Two trials of AZD7442 will enrol over 6,000 adults for the prevention of COVID-19 with additional trials enrolling ∼4,000 adults for the treatment of SARS-CoV-2 infections
US Government to invest ∼$486m for development and supply of up to 100,000 doses and can acquire another one million doses
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AstraZeneca's long-acting antibody (LAAB) combination, AZD7442, will advance into two Phase III clinical trials in more than 6,000 participants at sites in and outside the US that are due to begin in the next weeks. The LAABs have been engineered with AstraZeneca's proprietary half-life extension technology to increase the durability of the therapy for six to 12 months following a single administration. The combination of two LAABs is also designed to reduce the risk of resistance developed by the SARS-CoV-2 virus.
The Company has received support of around $486m from the US Government for the development and supply of AZD7442 under an agreement with the Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response at the US Department of Health and Human Services, and the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense.
One trial will evaluate the safety and efficacy of AZD7442 to prevent infection for up to 12 months, in approximately 5,000 participants. The second trial will evaluate post-exposure prophylaxis and pre-emptive treatment in approximately 1,100 participants.
AstraZeneca is planning additional trials to evaluate AZD7442 in approximately 4,000 patients for the treatment of COVID-19.
AstraZeneca plans to supply up to 100,000 doses starting towards the end of 2020 and the US Government can acquire up to an additional one million doses in 2021 under a separate agreement.
Pascal Soriot, Chief Executive Officer, said: "This agreement with the US Government will help accelerate the development of our long-acting antibody combination which has the potential to provide immediate and long-lasting effect in both preventing and treating COVID-19 infections. We will be evaluating the LAAB combination in different settings from prophylaxis, to outpatient treatment to hospitalisation, with a focus on helping the most vulnerable people."
LAABs mimic natural antibodies and have the potential to treat and prevent disease progression in patients already infected with the virus, as well as to be given as a preventative intervention prior to exposure to the virus. A LAAB combination could be complementary to vaccines as a prophylactic agent, e.g. for people for whom a vaccine may not be appropriate or to provide added protection for high-risk populations. It could also be used to treat people who have been infected.
Today's agreement builds on previous funding of more than $25m from US government agencies BARDA and the Defense Advanced Research Projects Agency for the discovery and evaluation of the monoclonal antibodies, as well as the Phase I clinical trial started in August 20201 to assess safety, tolerability and pharmacokinetics of AZD7442 in healthy individuals.
Financial considerations
The agreement is not anticipated to impact the Company's financial guidance for 2020 as the US Government funding is being offset by expenses to progress the clinical trials of AZD7442 as well as manufacturing process and upscaling costs. Should the Phase III trials prove successful and AZD7442 become an approved medicine, the Company anticipates providing the medicine at commercial terms during and after the current coronavirus pandemic.
AZD7442
AZD7442 is a combination of two LAABs derived from convalescent patients after SARS-CoV-2 infection. Discovered by Vanderbilt University Medical Center and licensed to AstraZeneca in June 2020, the LAABs were optimised by AstraZeneca with half-life extension and reduced Fc receptor binding. The half-life extended LAABs should afford six to 12 months of protection from COVID-19.2-5 The reduced Fc receptor binding aims to minimise the risk of antibody-dependent enhancement of disease - a phenomenon in which virus-specific antibodies promote, rather than inhibit, infection and/or disease.6
In a recent Nature publication, the LAABs were shown in pre-clinical experiments to block the binding of the SARS-CoV-2 virus to host cells and protect against infection in cell and animal models of disease.7
AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.
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References
1. ClinicalTrials.gov. NCT04507256. https://clinicaltrials.gov/ct2/show/NCT04507256?term=NCT04507256&draw=2&rank=1.
2. Robbie, G.J., et al., A novel investigational Fc-modified humanized monoclonal antibody, motavizumab-YTE, has an extended half-life in healthy adults. Antimicrob Agents Chemother, 2013. 57(12): p. 6147-53.
3. Griffin, M.P., et al., Safety, Tolerability, and Pharmacokinetics of MEDI8897, the Respiratory Syncytial Virus Prefusion F-Targeting Monoclonal Antibody with an Extended Half-Life, in Healthy Adults. Antimicrob Agents Chemother, 2017. 61(3).
4. Yu, X.Q., et al., Safety, Tolerability, and Pharmacokinetics of MEDI4893, an Investigational, Extended-Half-Life, Anti-Staphylococcus aureus Alpha-Toxin Human Monoclonal Antibody, in Healthy Adults. Antimicrob Agents Chemother, 2017. 61(1).
5. Domachowske, J.B., et al., Safety, Tolerability and Pharmacokinetics of MEDI8897, an Extended Half-life Single-dose Respiratory Syncytial Virus Prefusion F-targeting Monoclonal Antibody Administered as a Single Dose to Healthy Preterm Infants. Pediatr Infect Dis J, 2018. 37(9): p. 886-892.
6. Van Erp EA, Luytjes W, Ferwerda G and van Kasteren PB. Fc-Mediated Antibody Effector Functions During Respiratory Syncytial Virus Infection and Disease. Front. Immunol. 2019. https://doi.org/10.3389/fimmu.2019.00548.
7. Zost SJ et al. Potently neutralizing human antibodies that block SARS-CoV-2 receptor binding and protect animals. Nature. 2020. DOI: 10.1038/s41586-020-2548-6.
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Adrian Kemp
Company Secretary
AstraZeneca PLC
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