HAE2 is similar to HAE1, but its Fc region was altered to reduce binding to Fc receptors

HAE2 is similar to HAE1, but its Fc region was altered to reduce binding to Fc receptors. in a 23-fold improvement in affinity. HAE2 is similar to HAE1, but its Fc region was altered to reduce binding to Fc receptors. As expected given the decreased binding to Fc receptors, systemic exposure to pre-formed HAE2:IgE complexes in mice was greater (six-fold) and distribution to the liver lower (four-fold) compared with HAE1:IgE RAD50 complexes. In monkeys, systemic exposure to HAE1 was comparable to that previously observed for omalizumab in this species, but required comparatively lower serum drug concentrations to suppress free IgE levels. HAE2 treatment resulted in 6-Thioguanine greater exposure and greater increase of total IgE, relative to HAE1, because of decreased clearance of HAE2:IgE complexes. Overall, these data suggest that increased binding affinity to IgE may provide a more effective therapeutic for asthma patients, and that retaining FcR binding of the anti-IgE antibody is usually important for removal of anti-IgE:IgE complexes. decreased modestly as doses increased (Table 1) and the apparent volume of distribution at steady-state (and Vss/F were significantly reduced (p 0.05) relative to HAE1. The mean half- life of both HAE1 and HAE2 appeared comparable and ranged from 7C12 d. Open in a separate window Physique?2. (A) Serum HAE1 concentration-time profiles following a single subcutaneous administration to juvenile cynomolgus monkeys. Data symbolize the imply SD of n = 6 animals/group. Closed circle, HAE1 7.5 mg/kg; closed dark gray triangle, 15 mg/kg; closed square, 30 mg/kg; closed diamond, 50 mg/kg; closed light gray triangle, 75 mg/kg; closed octagon, 100 mg/kg; open circle, 200 mg/kg; closed black triangle, 250 mg/kg. Black solid collection represents the limit of quantitation (LOQ) in the HAE1 ELISA ( 0.160 g/mL). (B) Serum total HAE2 concentration-time profiles following a single subcutaneous administration to juvenile cynomolgus monkeys. Data symbolize the imply SD of n = 6 animals/group. Closed circle, HAE2 30 mg/kg; closed triangle, 50 mg/kg; closed square, 100 mg/kg; closed diamond, 250 mg/kg. Black solid collection represents the limit of quantitation (LOQ) in the HAE2 ELISA ( 0.160 g/mL). Table 1. Non compartmental pharmacokinetic parameter estimates (mean SD) following a single SC bolus of HAE1 or HAE2 to juvenile cynomolgus monkeys thead th align=”left” valign=”top” rowspan=”1″ colspan=”1″ Dose (mg/kg) hr / /th th align=”left” valign=”top” rowspan=”1″ colspan=”1″ CL/F (mL/day/kg) hr / /th th align=”left” valign=”top” rowspan=”1″ colspan=”1″ Vss/F (mL/kg) hr / /th th align=”left” valign=”top” rowspan=”1″ colspan=”1″ t1/2, elim (day) hr / /th th colspan=”4″ align=”center” valign=”top” rowspan=”1″ HAE1 /th /thead 7.5 hr / 7.9 4.3 hr / 75 10 hr / 6.8 4.1 hr / 15 hr / 6.5 5.1 hr / 68 16 hr / 7.8 42 hr / 30 hr / 4.4 0.9 hr / 62 7.7 hr / 7.1 4.1 hr 6-Thioguanine / 50 hr / 5.1 1.7 hr / 63 7.6 hr / 8.4 4.7 hr / 75 hr / 3.1 0.5 a hr / 42 4.3 b hr / 6.6 4.7 hr / 100 hr / 2.5 0.4 b hr / 37 2.9 b hr / 9.1 5.1 hr / 200 hr / 2.8 0.6 b hr / 52 4.9 b hr / 10 4.5 hr / 2503.4 0.8 a50 10 b8.6 6.0 Open in a separate window thead th colspan=”4″ align=”center” valign=”top” rowspan=”1″ HAE2 /th /thead 30 hr / 3.0 1.1 d hr / 46 10 d hr / 9.0 4.9 hr / 50 hr / 3.2 0.5 d hr / 51 6.2 d hr / 7.0 4.0 hr / 100 hr / 1.9 0.2 c hr / 31 4.5 c, d hr / 7.6 2.9 hr / 2502.4 0.3 c38 3.7 c, d12 4.3 Open in a separate window CL/F, clearance; t1/2,elim, elimination half life; Vss/F, volume of distribution at constant state. Note: n = 6/group. 6-Thioguanine ap 0.05 compared with HAE1 7.5 and 15 mg/kg dose groups. bp 0.05 compared with HAE1 7.5, 15, 30 and 50 mg/kg dose groups. cp 0.05 compared with HAE2 30 and 50 mg/kg dose groups. dp 0.05 compared with HAE1 at equivalent dose. Serum total IgE levels were highly variable throughout the study but increased significantly (p 0.05) following administration of HAE1 or HAE2 and remained elevated relative to placebo for the majority of the study (Fig.?3A and ?and3B).3B). In animals given HAE1, the mean maximal increase in total IgE was 13- to 43-fold above baseline (IgEmax/Bsl IgE) across dose levels and fell to ~5 to 10-fold above baseline at most dose levels at the end of the study (IgElast/Bsl IgE). In animals given HAE2, the magnitude of the total IgE response was significantly greater than that observed for HAE1 where the maximal increase in total IgE was 30- to 112-fold above baseline (IgEmax/Bsl IgE) and ~20-fold above baseline at the end of the study (IgElast/Bsl IgE). For both HAE1 and HAE2, no obvious or significant dose response relationship was seen (Table 2). Open in a separate window Physique?3. (A) Serum total IgE concentration-time profiles following a single subcutaneous administration of HAE1 to juvenile cynomolgus monkeys. Data symbolize the imply SD of n = 6 animals/group. Open triangle, control; Closed circle, HAE1 7.5 mg/kg; closed dark gray triangle, 15.