Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer death in American men. Most patients with metastatic disease respond initially to androgen deprivation therapy (ADT) but almost inevitably progress to castration-resistant prostate cancer (CRPC). Identification of markers and drivers of Metastatic CRPC (mCRPC) that (a) represent a progenitor-type cancer cell population, (b) persist in castration-resistant disease, (c) are actionable targets expressed on the cell surface, and (d) are induced by hypoxia is required to facilitate the development of novel targeted therapies. We identified prostatic acid phosphatase (PAP), particularly the transmembrane form (TMPAP), as one such potential target. PAP is both a phosphatase and a 5′ectonucleotidase that generates adenosine. PAP is a human tumor marker first described in 1936 and is still used as an important prognostic marker for advanced metastatic prostate cancer. Our group recently reported that the transmembrane form of the protein (TMPAP) is expressed in CRPC and can serve as a potential therapeutic target. We identified a lead human anti-TMPAP antibody clone 3D8 (3D8-Ab). 3D8-ADCs (Antibody Drug Conjugates) and 3D8-Ab were tested for their ability to reduce tumor size/volume in a xenograft model. The human PAP-expressing PCa cell line VCaP, originally derived from a vertebral metastasis from a patient with CRPC, was inoculated subcutaneously into SCID mice. Treatment with either 3D8-Ab or 3D8-ADC significantly reduced tumor size and increased animal survival. These data indicate that targeting PAP with monoclonal antibodies either alone or conjugated to toxins has the potential to treat CRPC.

BK polyomavirus (BKV) causes polyomavirus-associated nephropathy (BKV-nephropathy) and polyomavirus-associated haemorrhagic cystitis following kidney transplantation and allogeneic haematopoietic stem cell transplantation. BKV strains consist of four distinct genotypes (BKV-I, -II, -III and -IV), with more than 80% of individuals seropositive for the BKV-I genotype and lower prevalences of infection or co-infection with the other genotypes. BKV-nephropathy occurs widely in immunosuppressed transplant recipients, with the recommended treatment including reduction of immunosuppressive drugs. High serum titres of BKV-neutralizing antibodies and treatment with BKV-neutralizing intravenous immunoglobulin are associated with reduced levels of BKV-DNAemia in kidney transplant recipients, suggesting anti-BKV antibodies can limit viral load. Thus, we set out to generate broadly neutralizing human mAbs against the viral protein 1 (VP1) major capsid protein of BKV genotypes I–IV using VelocImmune ^® transgenic mice that encode for human immunoglobulins. Hybridoma clones from VelocImmune ^® mice immunized with combinations of BKV I–IV VP1 and respective genotypes of BKV pseudoviruses (BK-PsVs) were screened using a high-throughput binding assay against BKV-I VP1 expressed in HEK-293 cells. The VP1-binding hybridoma clones were then assessed for neutralization with BK-PsV consisting of respective VP1 proteins from BKV-I, -II, -III or -IV on the virion surface. Overall, 36 broadly cross-neutralizing mAbs against BKV-I, -II, -III and -IV were identified. Importantly, 20 of the cross-reactive immunoglobulins were subjected to nucleotide sequencing, resulting in 6 clonotype families with 14 genetically distinct immunoglobulins. Several of the most effective mAbs were fully humanized with the IgG1 Fc domain with broad neutralization of BK-PsV-I, -II, -III and -IV genotypes with IC50s ranging from ~7 to 200 pM. Thus, these cross-neutralizing mAbs represent potential biologics to be developed into BKV therapeutics.