Human Monoclonal Antibodies: a New Therapeutic Strategy against BK virus Infection and Associated Diseases – HuMABK

BK virus (BKV) infection has a major negative impact on the transplant recipient community. It is estimated that up to 30% of the 60,000 kidney transplants performed annually worldwide are potentially compromised by BKV-associated nephropathy (BKVAN) or BKV replication. Furthermore, prolonged BKV replication increases the risk of urothelial carcinoma in kidney transplant recipients. In addition, BKV infection causes symptomatic hemorrhagic cystitis in approximately 5% of the 50,000 hematopoietic stem cell transplants performed annually worldwide, and in 5% of cancer patients treated with high dose cyclophosphamide. No BKV-specific antiviral therapies are available, thus there is an urgent need to develop new anti-BKV preventive and therapeutic strategies.
Recently, we performed a prospective longitudinal study involving 168 kidney transplant recipients, prospectively followed over 24 months, and 69 donors. We demonstrated for the first time that kidney recipients with a strong BKV neutralizing antibody (Ab) response are protected against BKV infection and associated diseases (Solis et al. JASN 2018). We further showed that intravenous immunoglobulins (IVIG) are a source of BKV neutralizing Ab, notably against genotype I BKV. Furthermore, in a pilot study, we demonstrated that IVIG administration increased neutralizing Ab titers and protected kidney transplant recipients against genotype I BKV but not against other genotypes, most likely due to the limited neutralizing Ab titers reached against this latter genotypes.
Overall, our data strongly support the potential benefit of passive administration neutralizing Abs as a preventive or therapeutic strategy against BKV infection, provided they are able to neutralize all BKV genotypes.
The aim of this project is to combine expertise on BKV infection and Ab responses to BKV (partner 1) with that on human Ab isolation and characterization (partner 2) in order to isolate potent and broad BKV neutralizing human monoclonal Abs. Through our previous study, we were able to identify 20 individuals termed elite BKV neutralizers, with high serum titers of anti-BKV neutralizing Abs directed against all BKV genotypes, and to initiate a biobank of patient-derived BKV strains.. The cohort of elite BKV neutralizers will provide an outstanding source for isolation of BKV bNAbs. We will perform specific memory B cell sorting and single cell PCR using a recent methodological approach that has proven extremely successful at isolating human mAbs against other viruses. Generated human mAbs will be deeply characterized in term of binding, neutralization potency and cross-reactivity against our virus panel, epitope and structure. Lead candidates will be selected and patented for further valorization. We are confident that the human mAbs generated will represent a potential therapeutic strategy with ideal drug-like properties combining high-affinity targeting of the virus, biological neutralizing activity and broad recognition of clinically relevant BKV variants. Furthermore, this approach will not only provide a potential new therapeutic strategy against BKV infection but will also yield highly valuable tools for the design of new BKV immunogens for further vaccine development.
Overall, our data from a close interaction between two disciplines: virology and clinical nephrology provided crucial and unique inputs on BKV-host interaction. The results led to the emergence of a new concept of BKV infection in renal transplantation: the potential benefit of broadly neutralizing Abs as a preventive or therapeutic strategy against BKV infection. The overarching goal of the present translational project is to develop these mAbs and to close the gap from bench to bedside.