Sacituzumab govitecan: breakthrough targeted therapy for triple-negative breast cancer

Introduction: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype associated with an increased risk of recurrence and cancer-related death. Unlike hormone receptor-positive or HER2-positive breast cancers, there are limited targeted therapies available to treat TNBC and cytotoxic chemotherapy remains the mainstay of treatment. Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate targeting Trop-2 expressing cells and selectively delivering SN-38, an active metabolite of irinotecan.

Areas covered: This review covers the mechanism of action, safety and efficacy of sacituzumab govitecan in patients with previously treated, metastatic TNBC. Additionally, efficacy data in other epithelial malignancies is included based on a PubMed search for ‘sacituzumab govitecan’ and ‘clinical trial’.

Expert opinion: Sacituzumab govitecan has promising anti-cancer activity in patients with metastatic TNBC previously treated with at least two prior lines of systemic therapy based on a single arm Phase I/II clinical trial. A confirmatory Phase III randomized clinical trial is ongoing. Sacituzumab govitecan has a manageable side effect profile, with the most common adverse events being nausea, neutropenia, and diarrhea. The activity of sacituzumab govitecan likely extends beyond TNBC with promising early efficacy data in many other epithelial cancers, including hormone receptor-positive breast cancer.     

Improved Cellular Delivery of Antisense Oligonucleotides Using Transferrin Receptor Antibody-Oligonucleotide Conjugates

This work is dedicated to the memory of the late Dr Ian Walker.     

Mutagenicity of benzo(a)pyrenyl-1-sulfate in the Ames test.

Comparison of the mutagenicity of nine isomeric benzo(a)pyrenyl [B(a)P] phenols conjugated with either sulfate or glucuronide was carried out using strain Salmonella typhimurium TA98. Of the nine conjugates tested, only B(a)P-1-sulfate was mutagenic. Accordingly, the mutagenicity of B(a)P-1-sulfate was compared with that of B(a)P and 1-hydroxybenzo(a)pyrene [B(a)P-1-OH] in the presence and absence of rat lung S9 and Aroclor-induced liver S9 with and without an NADPH-generating system. B(a)P-1-sulfate was slightly mutagenic, whereas B(a)P and the 1-hydroxy derivative were nonmutagenic when S9 fractions and NADPH were omitted. Addition of induced liver S9 with NADPH caused mutagenicity with B(a) -1-OH greater than B(a)P greater than B(a)P-1-sulfate. B(a)P-1-sulfate was the only mutagenic species when lung S9 was added. This mutagenicity did not require NADPH. Sodium sulfite, an inhibitor of arylsulfatase, decreased the mutagenicity of B(a)P-1-sulfate. These data suggest that a unique mutagenic species is generated from B(a)P-1-sulfate via arylsulfatase in rat lung.     

Single-dose pharmacokinetics of paracetamol and its conjugates in Chinese non-insulin-dependent diabetic patients with renal impairment

Objective: A single oral dose of paracetamol (20 mg · kg⁻¹) was given to 38 Chinese patients with non-insulin-dependent diabetes mellitus (NIDDM) who had either normal renal function or varying degrees of renal impairment, with creatinine clearances ranging from 4 to 123 ml · min⁻¹ · 1.73 m⁻². The plasma and urinary concentrations of paracetamol and its major metabolites were measured by high-performance liquid chromatography (HPLC). Results: The absorption and elimination of paracetamol were unaffected by renal impairment. However, the area under the plasma concentration time curve and the elimination half-life of paracetamol metabolites increased significantly with worsening renal insufficiency. Mean renal clearances of paracetamol and its conjugates were significantly reduced in these subjects. There was no evidence of altered metabolic activation with renal impairment. Conclusion: The results demonstrate that paracetamol disposition is minimally affected by diabetic nephropathy; however, extensive accumulation of conjugates may occur. Received: 2 September 1996 / Accepted in revised form: 11 December 1996     

Endocrinology: Substrate dependency of C19 conjugates in hirsute hyperandrogenic women and the influence of adrenal androgen

Serum C₁₉ conjugates, specifically 3-androstanediol glucuronide(3G), reflect peripheral androgen action through the actionof 5-reductase activity. The origin of 5-reduced C₁₉ conjugateshas been controversial and it has been suggested that they arederived primarily from adrenal androgens. We examined concentrationsof 3G, 3-androstanediol sulphate (3S), androsterone glucuronide(AoG) and androsterone sulphate (AoS) in 40 hirsute hyperandrogenicwomen. These patients were divided into four groups based uponindividual, combined or normal concentrations of the adrenalandrogens dehydroepiandrosterone (DHEAS) and 11-hydroxy-androstenedione.Testosterone, unbound testosterone and androstenedione weresimilar in these groups. Serum 3G was equally high in all groupsand was correlated significantly with hirsutism, while the otherconjugates were not. Androsterone glucuronide was raised inall groups but was higher in patients with raised DHEAS. Serum3S was raised in all groups and was higher where both adrenalandrogens were raised. Serum AoS was highly correlated withDHEAS. Serum 3G was correlated with unbound testosterone andandrostenedione but not with the adrenal androgens. The glucuronideconjugates were correlated with one another as were the sulphateconjugates but glucuronides and sulphates were not correlated.These data confirm ovarian and adrenal dependency of C₁₉ conjugates.Serum 3G appears to reflect hirsutism most accurately and isleast dependent on adrenal androgens in patients with mixedhyperandrogenism.     

Variants of lymphoid lines produced with ricin A-chain monoclonal antibody conjugates

Conjugates of ricin A-chain with monoclonal anti-light chain antibodies specifically killed cells hearing kappa or lambda immunoglobulin (Ig) light chains. Exposure of cells from B-lymphoblastoid cell lines (B-LCL) to conjugate for less than 30 h had only a slight effect on cell growth, but on 48 h exposure a marked killing effect was achieved. After recovery of growth, cells were re-exposed to conjugate for 9-14 days. Treatment of cells from the EB4 line (sIgG lambda) in this way yielded 4 variants which showed a marked reduction in levels of surface Ig lambda and secreted Ig lambda with slight, or no, reduction in MHC class II expression and similar growth rates to the parent line. Variant lines retained their phenotype over long periods of culture.     

Interaction of antithrombin III with preadsorbed albumin-heparin conjugates

The adsorption of antithrombin III (AT III) onto polystyrene surfaces preadsorbed with albumin or albuminheparin conjugates was studied using a two step enzyme immuno assay. When AT III-buffer solutions were used, the highest adsorption values were measured on high affinity albumin-heparin conjugate pretreated surfaces. Less AT III adsorption was found on nonfractionated albumin-heparin conjugate preadsorbed surfaces. AT III adsorption could also be detected on low affinity conjugate and albumin coated surfaces. When AT III was adsorbed from plasma or plasma dilutions with buffer, only AT III on surfaces preadsorbed with high affinity or nonfractionated albumin-heparin conjugate was found. These results demonstrate that the heparin moiety of the conjugate is directed to the solution phase whereas the albumin moiety contacts the polystyrene surfaca