Complement receptor 1 (CR1, CD35) and complement receptor 2 (CR2, CD21) have been implicated as regulators of B-cell activation. We explored the role of these receptors in the development of humoral immunity by generating CR1-and CR2-deficient mice using gene-targeting techniques. These mice have normal basal levels of IgM and of IgG isotypes. B-and T-cell (14)(15)(16)(17)(18). Experiments using the T-cell-dependent antigens from sheep red blood cells (SRBC) and keyhole limpet hemocyanin have suggested that the primary immune response deficit in mice treated with anti-mouse CR1 and CR2 mAb can be overcome by using high doses of the immunogen (14).Here we have further explored the role of these receptors in the development of humoral immunity by generating CR1-and CR2-deficient mice using gene targeting. Our data show that CR1 and CR2 play important roles in the B-cell response and are necessary for appropriate B-cell activation and Ab production at both low and high doses of antigen. In addition, we demonstrate that germinal center formation is retained in the absence of these proteins. These mice should provide an excellent model to study in detail the specific roles of CR1 and CR2 in the immune response.

Background DS-8201a is a HER2 targeting antibody-drug conjugate (ADC) with high drug to antibody ratio (8:1), a novel linker and topoisomerase I inhibitor as the payload. In preclinical studies, DS-8201a showed efficacy against both trastuzumab emtansine (T-DM1) resistant HER2 positive breast cancer (BC) and against BC with low HER2 expression. The current phase 1 trial is comprised of dose escalation (Part 1) and dose expansion (Part 2) cohorts including patients (pts) with BC, gastric cancer and other HER2 expressing tumors. Only the results from BC cohorts are presented here. Methods Part 1 used a modified continual reassessment model to identify the recommended phase 2 dose (RP2D) of DS8201a in pts with BC or gastric cancer of any HER2 status. Two out of planned 4 expansion cohorts included BC: T-DM1-treated HER2 positive BC (Cohort 2a; IHC 3+ or IHC 2+/ISH +) and HER2 low BC (Cohort 2c, IHC 2+/ISH- or IHC 1+). Efficacy endpoints of objective response rate (ORR), disease control rate (DCR: CR + PR + SD), durability of response, progression free survival (PFS) and adverse events (AEs) were assessed. Results Overall, 146 subjects were included (24 Part 1; 122 Part 2). DS-8201a was administered up to 8.0 mg/kg in Part 1 without any DLTs, maximum tolerated dose was not reached. Based on available results, the dose levels of 5.4 and 6.4 mg/kg IV every 3 weeks were chosen for Part 2. In Part 2, a total of 56 BC pts were enrolled; 46 pts in Cohort 2a and 10 pts in Cohort 2c. The median age was 56 and number of prior regimens in the metastatic setting was 5 (range: 1-16). 37 BC pts had follow-up imaging scans and were evaluable for response at the time of data cutoff. Confirmed ORR was 41% (15/37) including 1 CR; DCR was 97% (36/37). The median duration of treatment was not reached. For Cohort 2a, where all pts had received prior T-DM1, treatment with DS-8201a achieved a higher ORR of 41% (11/27) and DCR of 100% (27/27) compared to the reported response these patients had to their prior T-DM1 treatment with ORR of 23% (5/22) and DCR of 73% (16/22). In the subset of 24 pts from cohort 2a who had received prior treatment with pertuzumab and T-DM1, the confirmed ORR was 44% (11/25). In Cohort 2c, confirmed ORR was 40% (4/10), DCR was 90% (9/10). Of the 46 BC pts in Part 2 who received at least one dose of DS-8201a, 4 pts discontinued treatment due to disease progression and 3 pts discontinued due to AE. The most common AEs of any grades were nausea, decreased appetite, vomiting, alopecia, and diarrhea. Only 2 pts experienced grade 4 AEs (thrombocytopenia and neutropenia) and 46 % (21/46) experienced grade 3 AEs (most commonly anemia, neutropenia, thrombocytopenia, leukopenia, lymphocytepenia, and vomiting). Conclusions DS-8201a was well tolerated and has significant activity in pts with T-DM1 and T-DM1/ pertuzumab pretreated HER2 positive BC and in pts with HER2 low BC, with durable disease control. Promising efficacy of this ADC in BC warrants further investigation. Citation Format: Modi S, Tsurutani J, Takahashi S, Iwata H, Park H, Redfern CH, Doi T, Li B, Iwasa T, Taira S, Hattori M, Ma CX, Fisher JM, Naito Y, Yonemori K, Kawasaki Y, Saito K, Jikoh T, Shahidi J, Lee CC, Yver A, Tamura K. Safety and efficacy results from a phase 1 study of DS-8201a in patients with HER2 expressing breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-07.