Biodistribution and efficacy of an anti-TENB2 antibody-drug conjugate in a patient-derived model of prostate cancer

// C. Andrew Boswell 1 , Daniela Bumbaca Yadav 1 , Eduardo E. Mundo 1 , 2 , Shang-Fan Yu 1 , Jennifer Arca Lacap 1 , Aimee Fourie-O’Donohue 1 , Katherine R. Kozak 1 , Gregory Z. Ferl 1 , Crystal Zhang 1 , Jason Ho 1 , Sheila Ulufatu 1 , Leslie A. Khawli 1 , 3 and Kedan Lin 1 , 4 1 Genentech Research and Early Development, South San Francisco, 94080 CA, USA 2 Present address: Department of Safety Assessment, Nektar Therapeutics, San Francisco, 94158 CA, USA 3 Present address: Department of Pathology and Laboratory Medicine, Keck School of Medicine of USC, Los Angeles, 90033 CA, USA 4 Present address: Clinical Development and US Operation, Innovent Biologics, South San Francisco, 94080 CA, USA Correspondence to: C. Andrew Boswell, email: boswell.andy@gene.com Keywords: antibody-drug conjugate; prostate cancer; pharmacokinetics; TENB2; imaging Received: August 01, 2019     Accepted: October 01, 2019     Published: October 22, 2019 ABSTRACT TENB2, a transmembrane proteoglycan protein, is a promising target for antibody drug conjugate (ADC) therapy due to overexpression in human prostate tumors and rapid internalization. We previously characterized how predosing with parental anti-TENB2 monoclonal antibody (mAb) at 1 mg/kg in a patient-derived LuCap77 explant model with high (3+) TENB2 expression could (i) block target-mediated intestinal uptake of tracer (< 0.1 mg/kg) levels of radiolabeled anti-TENB2-monomethyl auristatin E ADC while preserving tumor uptake, and (ii) maintain efficacy relative to ADC alone. Here, we systematically revisit this strategy to evaluate the effects of predosing on tumor uptake and efficacy in LuCap96.1, a low TENB2-expressing (1+) patient-derived model that is more responsive to ADC therapy than LuCap77. Importantly, rather than using tracer (< 0.1 mg/kg) levels, radiolabeled ADC tumor uptake was assessed at 1 mg/kg – one of the doses evaluated in the tumor growth inhibition study – in an effort to bridge tissue distribution (PK) with efficacy (PD). Predosing with mAb up to 1 mg/kg had no effect on efficacy. These findings warrant further investigations to determine whether predosing prior to ADC therapy might improve therapeutic index by preventing ADC disposition and possible toxicological liabilities in antigen-expressing healthy tissues.