Abstract 3619: Tolerability in mice, monkeys, and rabbits of new antibody (MAb)-drug (SN-38) immunoconjugates
Authors: Goldenberg David M. , Sharkey Robert M. , Founds Henry W. , Trisal Preeti , Tat Fatma , Govindan Serengulam V. , Cardillo Thomas M. 
Published: June 2012

Antibody drug conjugates (ADCs) of the topoisomerase I inhibitor, SN-38, that allowed for a slow release of SN-38 from the ADC over time, were prepared using anti-CEACAM5 MAb, labetuzumab (hMN-14), anti-TROP-2 MAb, hRS7, and other MAbs by thiol-maleimide conjugation chemistry. These were shown previously to have significant anti-tumor activity in human cancer-xenograft models at cumulative doses frequently ≤ 100 mg/kg (≤ 8 mg/kg human equivalent dose; HED) without toxicity. To determine tolerability and dose-limiting toxicity, hRS7-SN-38 was examined in Swiss-Webster (S-W) mice and Cynomolgus monkeys (CMs), and labetuzumab-SN-38 was evaluated in New Zealand White rabbits. CMs do not express CEACAM5, but similarity in tissue cross-reactivity of hRS7 renders toxicity evaluation of hRS7-SN-38 conjugates in CM feasible. Male S-W mice (n = 14; ∼ 40 g) were administered i.p with 0 (control), 250, 500, or 750 mg/kg (0, 4, 8, and 12 mg/kg SN-38 equivalents) of hRS7-SN-38 on days 1 and 4. Half of the animals were necropsied 7 d, and the remainder 15 d, after the last dose. Blood counts, serum chemistry, and histopathology were performed. This ADC was also administered to CMs (3 M + 3 F/group), via i.v. infusion, at 0, 60, or 120 mg/kg (0, 0.96 and 1.92 mg/kg SN-38 equivalents, respectively) on days 1 and 4. Two males and 2 females from each group were euthanized and necropsied day 11, while the remaining animals were terminated on day 32. Blood counts and chemistries were collected pre-study and periodically through termination. The labetuzumab-SN-38 conjugate was examined in rabbits (n = 6-10) at 0, 30, 60, and 90 mg/kg, administered on days 1 and 4. Mice experienced no hematopoietic toxicity, and only transient weight loss of &lt;10%, but there was a transient elevation in ALT and AST 7 days after treatment, which resolved in most animals one week later. There was no evidence of organ damage. Thus, mice tolerated a cumulative dose of 1500 mg/kg (HED ∼120 mg/kg) of the ADC. CMs receiving 2×60 mg/kg (HED = 2×20 mg/kg) had &lt;7.3% weight loss, showed no abnormal serum chemistries, and while blood counts decreased, they remained within normal limits. Histopathological changes in the terminal group ranged from mild to moderate, but trended to normalcy in the recovery group. The 2×120 mg/kg (HED = 2×40 mg/kg) dose resulted in severe GI and hematologic toxicity. Rabbits tolerated labetuzumab-SN-38 conjugate at all the doses (HED up to 2×30 mg/kg), with uneventful histopathology findings. Pharmacokinetic analysis of rabbit serum showed the IgG cleared with a half-life of ∼ 2 d, and SN-38 clearance was consistent with in vitro stability of the ADC in rabbit serum. ADC and free SN-38 were found to have similar mechanisms of action in vitro. These findings, coupled with previous efficacy studies in xenograft models, indicate a favorable therapeutic window for these ADCs and support the clinical evaluation of these agents in their appropriate indications.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3619. doi:10.1158/1538-7445.AM2011-3619