4.22. Macromolecules: Thymalfasin, Lactoferrin, TY027, and XAV-19
Thymalfasin (thymosin-α1, Zadaxin) is a 28-amino acid synthetic peptide that is identical to the natural thymosin-α1 produced by the thymus gland [290]. It possesses immunoregulatory properties owing primarily to its ability to activate various immune cells, particularly T cells. It is used alone or in combination with INFs as an immunomodulator for the treatment of chronic HBV and HCV infections [291,292]. Thymalfasin can also be used for the treatment of chemotherapy-induced immune suppression, and to increase the efficacy of HBV and influenza virus vaccines [293]. Currently, it is being tested in few clinical trials in the context of COVID-19. An important study is the trial to prevent COVID-19 infection in elderly renal dialysis patients (NCT04428008; n = 240).
Lactoferrin is another macromolecule that is being considered in the context of COVID-19. It is an iron-binding, multifunctional globular glycoprotein that is widely present in secretory biological fluids, particularly milk [294]. Lactoferrin exhibits a broad-spectrum antimicrobial activity against bacterial, viral, and fungal infections. It also appears to exhibit a clinically relevant activity against some forms of cancer [295], cystic fibrosis [296], and necrotizing enterocolitis [297]. Literature indicates that lactoferrin exhibits activity against a wide range of RNA and DNA viruses, including cytomegalovirus, herpes simplex viruses, HIV, HCV, poliovirus, hantaviruses, rotaviruses, human respiratory syncytial virus, and others [298,299]. Importantly, lactoferrin also appears to exhibit activity against SARS-CoV. It was shown that lactoferrin prevented SARS-CoV from entering human cultured cells. Lactoferrin appeared to block the interaction between the viral spike S protein and heparan sulfate proteoglycans, which serve as an anchoring site on the host cell surface during the early phase of virus infections [300]. Lactoferrin was also found to support the growth of the gut flora as well as the enterocytes proliferation with direct anti-inflammatory/immunomodulatory effects [301]. Currently, lactoferrin is being tested in few clinical trials for COVID-19, including liposomal lactoferrin in COVID-19 patients with mild-to-moderate disease as well as in asymptomatic COVID-19 patients (NCT04475120; n = 60).
Other antiviral macromolecules that are being tested against COVID-19 include TY027, a monoclonal antibody (NCT04429529; n = 25), and XAV-19, a heterologous swine glyco-humanized polyclonal antibody raised against the spike S protein of SARS-CoV-2 (NCT04453384; n = 368).
Lastly, other strategies are being clinically evaluated to treat COVID-19 patients as they may produce direct or indirect antiviral effects. These include the use of convalescent plasma (hyperimmune plasma) from fully recovered individuals [302], immunoglobulins, INFs (such as INF β-1a, INF β-1b, pegylated INF γ-1a and others) [303,304], RNA virus-based gene vector (such as DeltaRex-G) (NCT04378244; n = 18), and mesenchymal stem cells [305]. Furthermore, several anti-inflammatory/immune-modulatory drugs, antithrombotic drugs, and vitamins (vitamins C and D) are also being tested to prevent and/or treat severe COVID-19 cases that may arise because of excessive inflammation and thrombotic complications. Most frequently tested anti-inflammatory/immunomodulatory agents are listed in Table 2. Antithrombotic agents that are most frequently being tested in clinical trials for COVID-19 patients are also listed in Table 3.