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.
Highlights
With four approvals and another ~80 in clinical development, antibody-drug conjugates (ADCs) represent an important class of therapeutics [1, 2]
We reported that predosing with parental antiTENB2 monoclonal antibody (mAb) resulted in reduced target-mediated drug distribution (TMDD) of a tracer (< 0.1 mg/kg) dose of radiolabeled ADC in mouse intestines without affecting uptake in LuCap77 tumor explants [20]
Predosing with antiTENB2 had little to no effect on blood PK (Figure 3), suggesting that the chosen ADC dose of 1 mg/kg was large enough to saturate the TENB2 expressed in murine intestine during the first three days after dosing, in contrast with the previously observed nonlinear clearance following a very low (< 0.1 mg/kg) tracer dose of the same radiolabeled ADC in both normal [21] and tumor-bearing [20] mice
Summary
With four approvals and another ~80 in clinical development, antibody-drug conjugates (ADCs) represent an important class of therapeutics [1, 2]. The intent of ADC therapy is to combine the antigen-specificity of antibodies with the potency of cytotoxic drugs [3, 4]. Aside from the approval of KadcylaTM (ado-trastuzumab emtansine) for the treatment of HER2-positive metastatic breast cancer [5], success in ADC therapy has largely been confined to hematologic cancers, prompting the continued pursuit of strategies to improve tumor specificity, and minimize normal tissue toxicity. The ability of ADC therapeutics to achieve desirable therapeutic indices hinges on the balance between specific delivery of toxic chemotherapeutics to tumors and minimizing the risk of side effects to normal tissues [6]. Thio-anti-TENB2-MCvc-PAB-MMAE is a humanized anti-TENB2 ThioMab [10] conjugated to a potent anti-mitotic auristatin drug, monomethyl auristatin E (MMAE) through a maleimidocaproyl-valine-citrulline-para-amino-benzyloxy carbonyl www.oncotarget.com (MC-vc-PAB) linker designed to be cleaved by lysosomal proteases [11]
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