Chemical Identity

Property	Value
Molecular Weight	~160 kDa (ADC)
Peptide Payload	SN-38 (irinotecan metabolite)
Linker	CL2A (acid-cleavable)
DAR	7.6
Target	Trop-2

Structure

Sacituzumab govitecan (Trodelvy) is a humanized anti-Trop-2 IgG1 antibody conjugated to SN-38 via a pH-sensitive CL2A linker. The high DAR (~7.6) delivers significant cytotoxic payload to Trop-2-expressing tumors. The linker is cleavable in acidic tumor microenvironment and lysosomes.

Mechanism of Action

The antibody binds Trop-2, a transmembrane glycoprotein overexpressed on many epithelial cancers. After internalization and lysosomal processing, SN-38 is released, inhibiting topoisomerase I and causing DNA strand breaks during replication. The hydrolyzable linker also allows local bystander killing.

Clinical Applications

• Triple-negative breast cancer: After two or more prior therapies (Trodelvy)
• HR+/HER2- metastatic breast cancer: After endocrine therapy
• Urothelial carcinoma: After platinum and PD-1/PD-L1 therapy
• Trop-2-expressing solid tumors: Under investigation

Pharmacokinetics

• Half-life: ~23 hours (total antibody)
• Cmax (SN-38): ~167 ng/mL
• Steady state: Cycle 1
• Metabolism: SN-38 metabolized by UGT1A1
• Route: IV infusion days 1, 8 of 21-day cycle (10 mg/kg)

Safety and Side Effects

Neutropenia (63%), diarrhea (59%), nausea (66%), fatigue (51%), alopecia (46%), anemia, and febrile neutropenia. UGT1A1*28 homozygotes at higher risk for toxicity. Premedication required.

References

• Bardia, A., et al. (2019). Sacituzumab govitecan for metastatic TNBC (ASCENT). New England Journal of Medicine, 384, 1529-1541.
• Tagawa, S.T., et al. (2021). TROPHY-U-01: sacituzumab govitecan for urothelial carcinoma. Journal of Clinical Oncology, 39, 2294-2303.