Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer

Abstract

Human kallikrein peptidase 2 (hK2) is a prostate specific enzyme whose expression is governed by the androgen receptor (AR). AR is the central oncogenic driver of prostate cancer (PCa) and is also a key regulator of DNA repair in cancer. We report an innovative therapeutic strategy that exploits the hormone-DNA repair circuit to enable molecularly-specific alpha particle irradiation of PCa. Alpha-particle irradiation of PCa is prompted by molecularly specific-targeting and internalization of the humanized monoclonal antibody hu11B6 targeting hK2 and further accelerated by inherent DNA-repair that up-regulate hK2 (KLK2) expression in vivo. hu11B6 demonstrates exquisite targeting specificity for KLK2. A single administration of actinium-225 labeled hu11B6 eradicates disease and significantly prolongs survival in animal models. DNA damage arising from alpha particle irradiation induces AR and subsequently KLK2, generating a unique feed-forward mechanism, which increases binding of hu11B6. Imaging data in nonhuman primates support the possibility of utilizing hu11B6 in man.

Genetic signature of prostate cancer resistant to optimized hK2 targeted alpha-particle therapy

“…In GEMM, the highest specific uptake of [ 225 Ac]hu11B6 was found in prostate lobes (Figure 3b). In summary, biodistribution profile of 1-step labeled [ 225 Ac]hu11B6 closely resembled our previously published results based on the 2-step labeled [ 225 Ac]hu11B6 compound 3 . Therefore, the one-step labelling protocol was used for all further studies.…”

“…The product was 98.5%  2.0% (n=5) radiochemically pure and the specific activity was 0.068 Ci/g ± 0.032 Ci/g (2.516 GBq/g ± 1.184 GBq/g; n=5). The radiochemical yields for the four hu11B6 combinations prepared using a two-step radiolabeling method were as follows: [ 225 Ac]hu11B6-IgG1 (native IgG1), 3 post-injection (Figure 1a). LNCaP-AR tumor models led to similar findings; [ 225 Ac]hu11B6-IgG3 R435H showed significantly (p=0.1653 at 4h, p=0.0003 at 72h, p=0.0132 at 240h p.i.)…”

“…Actinium-225 labeled antibodies and small molecules targeting prostate specific antigen (PSMA) are currently being evaluated in clinical trials, and reports have already shown promising therapeutic results in prostate cancer (PCa) patients resistant to androgen receptor (AR)-inhibiting drugs [1][2][3] . Unfortunately, toxicities generated by off-target accumulation in radio-sensitive tissues, such as salivary glands and kidneys, is of growing concern 4,5 .…”

“…Our group has previously reported on the targeting specificity, efficacy and biological response of radiolabeled hu11B6 as an immunotheranostic vehicle. Preclinical evaluations have been carried out in multiple immunodeficient and immunocompetent, rodent disease models as well as in non-human primates 3,[11][12][13][14] . In addition, studies of the uptake mechanism have revealed that hu11B6 is internalized by hK2 expressing cells via a mechanism driven by the neonatal Fc receptor (FcRn); while uncomplexed hu11B6 is released from the cell by recycling endosomes after binding to FcRn, the hu11B6-hK2 complex is routed to lysosomes for processing 12 .…”

“…In addition, studies of the uptake mechanism have revealed that hu11B6 is internalized by hK2 expressing cells via a mechanism driven by the neonatal Fc receptor (FcRn); while uncomplexed hu11B6 is released from the cell by recycling endosomes after binding to FcRn, the hu11B6-hK2 complex is routed to lysosomes for processing 12 . The proximity of the internalized radionuclide-labeled hu11B6 to the nucleus results in efficient cell kill, which is further accelerated by inherent AR and hK2 upregulation related to DNA-repair 3 .…”