29 research outputs found
New Antibody Conjugates in Cancer Therapy
Targeting of radiation, drugs, and protein toxins to cancers selectively with monoclonal antibodies (MAbs) has been a topic of considerable interest and an area of continued development. Radioimmunotherapy (RAIT) of lymphoma using directly labeled MAbs is of current interest after approval of two radiolabeled anti-CD20 MAbs, as illustrated with the near 100% overall response rate obtained in a recent clinical trial using an investigational radiolabeled anti-CD22 MAb, 90Y-epratuzumab. The advantage of pretargeted RAIT over directly labeled MAbs is continuing to be validated in preclinical models of lymphoma and solid tumors. Importantly, the advantages of combining RAIT with radiation sensitizers, with immunotherapy, or a drug conjugate targeting a different antigen are being studied clinically and preclinically. The area of drug-conjugated antibodies is progressing with encouraging data published for the trastuzumab-DM1 conjugate in a phase I clinical trial in HER2-positive breast cancer. The Dock-and-Lock platform technology has contributed to the design and the evaluation of complex antibody-cytokine and antibody-toxin conjugates. This review describes the advances made in these areas, with illustrations taken from advances made in the authors' institutions
Sacituzumab Govitecan (IMMU-132) in treatment-resistant uterine serous carcinoma: A case report
Background: Uterine serous carcinoma (USC) is a biologically aggressive variant of uterine cancer. Effective treatment options for recurrent, chemotherapy-resistant USC are extremely limited. Case: We describe a 74-year-old woman with recurrent and widespread treatment-resistant disease, who experienced a dramatic response to sacituzumab govitecan, a novel antibody-drug conjugate (ADC) targeting human trophoblast-cell-surface antigen (TROP-2), after failing multiple chemotherapy and immunotherapy. The impressive clinical response (66% reduction of target lesions by RECIST 1.1 with a duration response of over 10 months) was confirmed with serial CT scans in the absence of significant adverse events. Conclusion: Sacituzumab govitecan may present a new treatment option for recurrent USC patients harboring Trop-2+ tumors resistant to chemotherapy. Clinical trials with sacituzumab govitecan are warranted. Keywords: Sacituzumab govitecan, IMMU-132, Uterine serous carcinoma, Recurrent, Treatment-resistan
Improving the Therapeutic Index in Cancer Therapy by Using Antibody–Drug Conjugates Designed with a Moderately Cytotoxic Drug
The
antibody–drug conjugate (ADC), IMMU-130, of the moderately
cytotoxic topoisomerase I inhibitor, SN-38, and the CEACAM5-targeted
humanized antibody (mAb), labetuzumab, was evaluated in model systems
of human colon carcinoma and in phase I clinical trials of heavily
pretreated patients with metastatic colorectal cancer. The conjugate,
designed with a near-homogeneous drug substitution of 7–8 SN-38/mAb
and with a linker that released 50% of the drug in ∼20 h, showed
significant antitumor effects compared to a nontargeted ADC in human
tumor xenografts, which could be augmented in combination with bevacizumab.
The advantage of fractionated dosing was demonstrated, with potential
implications for the clinical dosing schedule. Biodistribution comparing
IMMU-130 with labetuzumab showed that the conjugate cleared somewhat
faster from the blood, but this did not affect tumor uptake and retention.
The use of an ultrastable linker in the conjugate design abrogated
antitumor effects. A tolerability study in rabbits showed a high safety
margin, with no-observed-adverse-effect level (NOAEL) corresponding
to a cumulative human-equivalent protein dose of 40–60 mg/kg.
The preclinical findings appear to be corroborated in two phase I
clinical trials, with high tolerability and evidence of antitumor
activity, including objective responses. The impact of the ADC design
on the utility of IMMU-130, tailored to a poorly internalizing target,
is discussed
Figure S7 from Improving Intracellular Delivery of an Antibody–Drug Conjugate Targeting Carcinoembryonic Antigen Increases Efficacy at Clinically Relevant Doses <i>In Vivo</i>
Spider plots of tumor growth. Nude mice bearing LS174T xenografts were injected with 4 doses of 10 mg/kg (marked with arrows on day 0, 4, 8, and 12) of either LG, XAb-SN-38, or vehicle. Individual growth curves for all mice are shown.</p