Abstract 2082: Fc-FcγR interaction impacts the clearance and antitumor activity of antibody-drug conjugates in NSG mice

Abstract

Abstract Majority of preclinical efficacy studies for cancer therapeutics are performed on tumor models implanted in immune-deficient mouse strains, including athymic nude, severe combined immunodeficiency (SCID), or NOD-SCID/IL2Rgamma null (NSG) mice. To better understand the correlation between drug exposure and preclinical antitumor activity of biologics, we evaluated the pharmacokinetic (PK) profiles of antibodies and antibody-drug conjugates (ADC) in four strains of mice commonly used in cancer research, including BALB/c, athymic nude, SCID, and NSG. To our surprise, antibodies and ADCs had an abnormally short serum half-life in NSG mice, compared to other strains of mice. We hypothesized that the fast clearance from plasma in NSG mice may reduce the overall exposure of xenografts to the ADCs, resulting in underestimation of antitumor activity. This was confirmed by comparing cAC10-vcMMAE in CD30+ Karpas-299 tumors implanted in either SCID mice or NSG mice. A single dose of 1 mg/kg cAC10-vcMMAE ADC resulted in complete remission of Karpas-299 tumors implanted in SCID mice (5/5). In contrast, the same treatment regimen had no effect on Karpas-299 tumors implanted in NSG mice (0/5). This observation suggests indeed the shortened exposure penalizes ADC efficacy in NSG models. We then hypothesized that the fast clearance of ADCs from plasma in NSG mice could be mediated by Fc-FcγR interaction; compromising this interaction may improve the serum half-lives of antibodies and ADCs and thus enhance ADC-mediated antitumor effects in NSG mice. To test this, we utilized a mutant antibody with the amino acid substitutions of E233P:L234V:L235 in its Fc domain that result in significantly reduced FcγR binding (G1V1). These mutations restored the serum exposure in NSG mice to that level comparable to other strains of mice. As a result, treatment of 1 mg/kg cAC10G1V1-vcMMAE led to tumor remission in Karpas-299 tumors grown in NSG mice, correlating with extended exposure. In parallel, pretreatment with human IV immunoglobulin also enhanced ADC exposure and antitumor activity in the NSG mice. In summary, these results suggest preclinical PK/PD assessment should be performed in the same strains of mice, especially when NSG xenograft models are used to evaluate activities. Moreover, reduced FcγR binding may enhance ADC exposure and allow a better assessment of therapeutic potential of biologics in NSG-based xenograft models. Citation Format: Fu Li, Michelle Ulrich, Joshua Hunter, Lori Westendorf, Devra Olson, Cassie Baker Lee, Dennis Benjamin, Che-Leung Law. Fc-FcγR interaction impacts the clearance and antitumor activity of antibody-drug conjugates in NSG mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2082.