Safety and Pharmacokinetic Studies of IMMU-132

Epithelial Cancers & MMU-132

Sacituzumab govitecan (IMMU-132) is an antitrophoblast surface antigen (anti-Trop-2) humanized antibody-SN-38 conjugate that is used clinically in the form of irinotecan. Although SN-38 is less potent than drugs used in other ADCs, preclinical testing in mouse models has shown that ADCs prepared with SN-38 are effective and have good performance when antibodies and linkers are carefully selected during the treatment window. Furthermore, studies on crab-eating worms showed that this ADC didn't cause significant damage to normal tissues expressing Trop-2, suggesting that this antigen is somehow protected in normal tissues or that normal tissues are protected by SN-38 The impact is small. Therefore, there is a need to explore the pharmacokinetics (PK) and safety assessment of MMU-132 in humans as early evidence of efficacy in the treatment of patients with multiple advanced epithelial cancers.

In this study, the scientists analyze the pharmacokinetics and safety of IMMU-132 at doses of 8 or 10 mg/kg over multiple cycles in patients with a variety of advanced epithelial cancers and conduct preliminary efficacy assessments.

See our ADC in vivo analysis:

• ADC Pharmacokinetics Characterization
• ADC In Vivo Efficacy Evaluation
• ADC Immunogenicity Analysis

Safety and Tolerability

• Adverse events were reported in 99% of patients in the 8 mg/kg cohort and 92% of patients in the 10 mg/kg cohort. The 10 mg/kg cohort had a slightly higher incidence of severe adverse events, including diarrhea, neutropenia, and febrile neutropenia. None of the patients experienced grade 4 diarrhea, but 4% of patients (1 at 8 mg/kg and 5 at 10 mg/kg) with grade 3 diarrhea were hospitalized.
• A higher percentage of patients in the 10 mg/kg cohort experienced severe neutropenia after the first dose compared to the 8 mg/kg cohort. After 1 or 2 doses, 50% of the 8 mg/kg group and 63% of the 10 mg/kg group reported severe neutropenia. The 8 mg/kg group had a slightly higher frequency of severe neutropenia after ≥3 doses.
• The uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) status of 146 patients in the 8 mg/kg and 10 mg/kg IMMU-132 cohorts was analyzed. A pie chart in Fig. 1 shows the percentage of patients with each haplotype who experienced grade ≥ 3 neutropenia or various grades of diarrhea during treatment. Dose-limiting neutropenia after the first cycle was not correlated with the UGT1A1 genotype.

Fig. 1. UGT1A1 haplotype status is illustrated in 146 patients who received IMMU-132 along with the incidence of neutropenia or diarrhea based on haplotype.¹

PK Parameters and Immunogenicity

Enzyme-linked immunosorbent assay (ELISA) was used to measure IMMU-132 (intact conjugate) and humanized anti-trophoblast cell-surface antigen-antibody immunoglobulin G (IgG), and reversed-phase high-performance liquid chromatography was used to determine the total and free levels of SN-38 and its glucuronidated form (SN-38G).

• IMMU-132 is cleared from the body at a faster rate compared to unconjugated anti-trophoblast cell-surface antigen IgG. The majority of SN-38 in the blood serum is bound to IgG, with only a small percentage of free SN-38 present, with median total SN-38 levels in the 10 mg/kg group of 4234 and 1334 ng/mL at 30 minutes and day 1, respectively, whereas free SN-38 levels were just 95.3 ng/mL (2.3%) and 56.9 ng/mL (4.5%) at these same times, respectively.
• The data also shows that SN-38 is largely protected from glucuronidation. In the 10 mg/kg group, the AUC for the glucuronidated free SN-38G was 1.5 ± 0.9 µg-hour/mL (n = 17) versus 2.9 ± 0.9 µg-hour/mL (n = 27) for the non glucuronidated form (average free SN-38G/free SN-38 AUC ratio = 0.52).
• Additionally, there was no evidence to suggest that neutropenia was correlated with the levels of free SN-38 initially in the serum (Fig. 2).

Fig. 2. Correlation of neutropenia (NAC) after the first dose of IMMU-132 to concentrations of free SN-38 is illustrated in the 30-minute serum sample.¹

Efficacy

The study analyzes the response rate of patients receiving different doses of IMMU-132 for four indications. Due to non-randomized enrollment, there were more patients at the 10 mg/kg dose level than at the 8 mg/kg dose level. The 10 mg/kg group had a higher objective response rate for three out of four indications compared to the 8 mg/kg group (Fig. 3). The clinical benefit rate, which combines objective responses and stable disease lasting a certain duration, was also higher for the 10 mg/kg group in three indications.

Fig. 3. Preliminary efficacy assessments are illustrated for 4 indications in patients with metastatic cancer who received IMMU-132 at a starting dose of either 8 or 10 mg/kg.¹

Overall, this study demonstrates that the pharmacokinetic profile of MMU-132 is consistent and that its toxicity at doses of 8 and 10 mg/kg can be effectively managed. Considering the positive treatment results and favorable therapeutic index at 10 mg/kg, this dose is expected to serve as a rational concentration to further advance development.

With extensive experience in the field of ADC development, Creative Biolabs offers our worldwide customers customized ADC development services for urothelial cancer and targeting TROP-2.

Reference

1. Ocean, Allyson J., et al. "Sacituzumab govitecan (IMMU‐132), an anti‐Trop‐2‐SN‐38 antibody‐drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics." Cancer 123.19 (2017): 3843-3854.

For Research Use Only. NOT FOR CLINICAL USE.