Abstract 1773: HPN424, a half-life extended, PSMA/CD3-specific TriTAC for the treatment of metastatic prostate cancer

Abstract

Metastatic, castrate-resistant prostate cancer (mCRPC) is diagnosed in up to 50,000 patients each year in the US alone, and roughly 27,000 patients will succumb to it every year. Once metastasized beyond regional lymph nodes, the 5-year survival rate is 30%. While novel therapeutics like abiraterone and enzalutamide have improved the treatment options for mCRPC, no curative treatment is available, and new therapies are urgently needed. HPN424 is a ~50-kDa antibody derivative called TriTAC (Tri-specific T cell Activating Construct) under development for the treatment of mCRPC. It is designed to simultaneously bind to CD3ε on T cells and to prostate specific membrane antigen (PSMA, FOLH1) on prostate cancer cells. A third domain of HPN424 binds non-covalently to serum albumin for extension of serum half-life. PSMA is expressed in >90% of malignant lesions of patients, and outside the central nervous system, its expression on normal tissue is largely restricted to the prostate. HPN424 binds human PSMA with sub-nanomolar affinity. When incubated in co-cultures with resting, human T cells and prostate cancer cells, it activates T cells and induces cytokine production, proliferation and redirected target cell killing with EC50 values in the single digit picomolar range. When administered to mice bearing human prostate cancer xenografts and human T cells, HPN424 eradicates subcutaneous tumors. The affinities of HPN424 for human and cynomolgus monkey CD3 and albumin are comparable, while HPN424 binds only marginally to cynomolgus PSMA. HPN424 is very well tolerated in non-human primates, even at high doses, indicating that CD3-binding has little if any pharmacological effect in the absence of target binding. Pharmacokinetic analysis supports weekly administration in humans. Our preclinical data suggest that HPN424 will be highly efficacious, safe and convenient for the treatment of patients with mCRPC. Citation Format: Bryan Lemon, Wade Aaron, Richard Austin, Patrick Baeuerle, Manasi Barath, Adrie Jones, Susan D. Jones, Kathryn Kwant, Che-Leung Law, Anna Muchnik, Kenneth Sexton, Laurie Tatalick, Holger Wesche, Timothy Yu. HPN424, a half-life extended, PSMA/CD3-specific TriTAC for the treatment of metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1773.

Prostate-specific Membrane Antigen Biology in Lethal Prostate Cancer and its Therapeutic Implications

“…Predictable and generally low-grade cytokine release syndrome was easily mitigated by dexamethasone premedication, prehydration, and a lower run-in dose. A trispecific T-cell-activating construct consisting of a PSMA-targeting domain, a CD3targeting domain, and a third domain that binds noncovalently to serum albumin to extend the half-life (HPN424) is also in phase 1 clinical development (NCT03577028)[69]. While in vitro studies of AMG160 indicated that PSMA expression is necessary for antitumour activity[70], the clinical trial did not select patients on the basis of PSMA expression[71,72].…”

Emerging new therapeutic antibody derivatives for cancer treatment

“…T cell-engaging BsAbs used for solid tumor treatment have been explored by targeting established tumor antigens, such as HER2, EpCAM, carcinoembryonic antigen (CEA), and PSMA. [124][125][126][127] Many preclinical studies have demonstrated that T cell-engaging BsAbs can induce sufficient activation of T cells and subsequent killing of tumor cells in various mouse xenograft tumor models. [128][129][130] To date, the most advanced T cell-engaging BsAbs that have entered clinical trials for investigation in patients are in phase I trials.…”

Bispecific Antibodies in Prostate Cancer Therapy: Current Status and Perspectives

“…The construct is generated in the so called TriTAC format (Tri-specific T cell-Activating Construct) and directed against CD3 and PSMA in a monovalent form ( Figure 3 D). In addition, it contains a specificity binding to human serum albumin (HSA) to prolong serum half-life [ 99 ]. The relatively large HSA molecule prevents excretion via the kidney, resulting in a reported half-life of approximately 80 h in cynomolgus monkeys [ 99 , 100 ].…”

“…In addition, it contains a specificity binding to human serum albumin (HSA) to prolong serum half-life [ 99 ]. The relatively large HSA molecule prevents excretion via the kidney, resulting in a reported half-life of approximately 80 h in cynomolgus monkeys [ 99 , 100 ]. Only the CD3 binding domain of this bsAb is a scFv fragment, whereas the HSA and PSMA specificities are provided by single camelid heavy chain variable domains [ 101 ].…”

“…Another issue with many bsAbs is the often low serum half-life [ 88 , 113 ], which, e.g., in the case of BiTE molecules, required the implementation of cumbersome continuous infusion protocols. Accordingly, several larger, IgG-based molecules like our IgGsc, the duobody format, or half-life extended versions of small constructs (e.g., by fusion to albumin [ 99 ] or to PEG derivatives [ 64 ]) are presently under development. In this context, the phenomenon of target mediated drug disposition (TMDD) must be considered, which results in accelerated serum elimination particularly at the—compared to mAbs—low doses at which bsAbs usually are applied [ 113 , 114 ].…”