Abstract
Evaluate the efficacy of an SN-38-anti-Trop-2 antibody-drug conjugate (ADC) against several human solid tumor types, and to assess its tolerability in mice and monkeys, the latter with tissue cross-reactivity to hRS7 similar to humans. Two SN-38 derivatives, CL2-SN-38 and CL2A-SN-38, were conjugated to the anti-Trop-2-humanized antibody, hRS7. The immunoconjugates were characterized in vitro for stability, binding, and cytotoxicity. Efficacy was tested in five different human solid tumor-xenograft models that expressed Trop-2 antigen. Toxicity was assessed in mice and in Cynomolgus monkeys. The hRS7 conjugates of the two SN-38 derivatives were equivalent in drug substitution (∼ 6), cell binding (K(d) ∼ 1.2 nmol/L), cytotoxicity (IC(50) ∼ 2.2 nmol/L), and serum stability in vitro (t/(½) ∼ 20 hours). Exposure of cells to the ADC demonstrated signaling pathways leading to PARP cleavage, but differences versus free SN-38 in p53 and p21 upregulation were noted. Significant antitumor effects were produced by hRS7-SN-38 at nontoxic doses in mice bearing Calu-3 (P ≤ 0.05), Capan-1 (P < 0.018), BxPC-3 (P < 0.005), and COLO 205 tumors (P < 0.033) when compared to nontargeting control ADCs. Mice tolerated a dose of 2 × 12 mg/kg (SN-38 equivalents) with only short-lived elevations in ALT and AST liver enzyme levels. Cynomolgus monkeys infused with 2 × 0.96 mg/kg exhibited only transient decreases in blood counts, although, importantly, the values did not fall below normal ranges. The anti-Trop-2 hRS7-CL2A-SN-38 ADC provides significant and specific antitumor effects against a range of human solid tumor types. It is well tolerated in monkeys, with tissue Trop-2 expression similar to humans, at clinically relevant doses, and warrants clinical investigation.
Highlights
Human trophoblast cell-surface antigen (Trop-2), known as GA733-1, EGP-1, and TACSTD2, is expressed in a variety of human carcinomas and has prognostic significance in some, being associated with more aggressive disease [1,2,3,4,5,6,7,8,9,10,11,12,13,14]
Exposure of cells to the antibody–drug conjugate (ADC) demonstrated signaling pathways leading to poly-ADP-ribose polymerase (PARP) cleavage, but differences versus free SN-38 in p53 and p21 upregulation were noted
We reported the preparation of antibody–drug conjugates (ADC) using an anti-CEACAM5 (CD66e) IgG coupled to several derivatives of SN-38, a topoisomeraseI inhibitor that is the active component of irinotecan, or CPT-11 [22, 23]
Summary
Human trophoblast cell-surface antigen (Trop-2), known as GA733-1 (gastric antigen 733-1), EGP-1 (epithelial glycoprotein-1), and TACSTD2 (tumor-associated calcium signal transducer), is expressed in a variety of human carcinomas and has prognostic significance in some, being associated with more aggressive disease [1,2,3,4,5,6,7,8,9,10,11,12,13,14]. Trop-2 antigen’s distribution in many epithelial cancers makes it an attractive therapeutic target, but its normal tissue expression profile casts some doubt on Trop-2 as a suitable target [11, 14]. Targeting and therapeutic efficacies were documented in a number of human tumor xenografts using radiolabeled RS7 [18,19,20], but this internalizing antibody did not show therapeutic activity in unconjugated form [18]. In vitro it has demonstrated antibody-dependent cellular cytotoxicity (ADCC) activity against Trop-2 positive carcinomas [21]
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