Abstract 2438: Efficacious therapies of two human pancreatic cancer xenografts and an aggressive human lymphoma xenograft with redesigned antibody-SN-38 conjugates (2010)

Abstract Antibody (MAb) conjugates of the potent topoisomerase I inhibitor, SN-38, have been previously shown by our groups to be efficacious in the targeted therapies of human cancer xenografts in nude mice. The conjugates have since been redesigned with a new bifunctional SN-38, ‘CL2A-SN-38’ (maleimido-[x]-Lys-PABOCO-20-O-SN-38, where PAB is p-aminobenzyl and ‘x’ contains a short PEG), without a cleavable dipeptide, to simplify process and improve quality. CL2A-SN-38 was conjugated to humanized MAbs, hRS7 (anti-EGP-1), hPAM4 (anti-mucin), hMN-14 (anti-CEACAM5), hLL2 (anti-CD22), and hA20 (anti-CD20). The conjugates, with a mean SN-38/MAb substitution of ∼ 6, were evaluated in the Capan-1 and BxPC-3 pancreatic human tumor xenografts and the Ramos human NHL tumor xenograft grown s.c. in female athymic nude mice. When the starting tumor sizes in animals reached 0.2 to 0.3 cm3, specific and non-targeting control conjugates were administered i.p. in a twice-weekly × 4 weeks schedule using 0.39 mg/kg (protocol-1) or 0.20 mg/kg (protocol-2) or 0.08 mg/kg (protocol 3) of SN-38 equivalent. Saline controls were included. In the therapy of Capan-1 xenograft (protocol 2; n = 10), specific targeting by SN-38 conjugates of hRS7, hPAM4, and hMN-14 produced significant tumor growth control versus control hA20-SN-38 conjugate on day 35 (AUC, P &amp;lt; 0.034), but there was no difference among the specific conjugates. Median survival time (MST) for untreated was 35 days, while MST was not reached on day 56 for treatments with all the three specific conjugates (protocol 2). In therapy in the BxPC-3 model (protocol 1; n = 10), MST for treatment with specific hRS7-SN-38 was significantly better than that for untreated or treatment with control hA20-SN-38 (P &amp;lt; 0.0006) or treatment with hMN-14-SN-38 (P &amp;lt; 0.0046). In the Ramos lymphoma model (n = 5), MST in untreated animals was only 7 days owing to rapid tumor growth, while MST was not reached on day 35 with the specific hLL2-SN-38 treatment (protocol 2). Moreover, combination of hA20 immunotherapy and hLL2-SN-38 immunoconjugate therapy (protocol 3) extended MST significantly versus conjugate treatment alone (P &amp;lt; 0.015). A dose of up to 47 mg/kg of SN-38 equivalent [240 mg/kg human equivalent protein dose of the conjugate], examined thus far, was very well tolerated in normal mice, as determined by blood counts and serum chemistries, which indicated an excellent therapeutic window. The redesigned conjugates, without the cathepsin B cleavable peptide, retained the efficacies of the CL2-SN-38-based conjugates, were monomeric, and were amenable to scale-up. These features, together with very favorable safety profiles, portend well for the clinical development of these immunoconjugates for different cancer indications. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2438.