Anti-Endosialin Antibody–Drug Conjugate: Potential in Sarcoma and Other Malignancies

Abstract

Endosialin/TEM1/CD248 is a cell surface protein expressed at high levels by the malignant cells of about 50% of sarcomas and neuroblastomas. The antibody-drug conjugate (ADC) anti-endosialin-MC-VC-PABC-MMAE was selectively cytotoxic to endosialin-positive cells in vitro and achieved profound and durable antitumor efficacy in preclinical human tumor xenograft models of endosialin-positive disease. MC-VC-PABC-MMAE was conjugated with anti-endosialin with 3-4 MMAE molecules per ADC. The anti-endosialin-MC-VC-PABC-MMAE conjugate was tested for activity in four human cell lines with varied endosialin levels. The HT-1080 fibrosarcoma cells do not express endosialin, A-673 Ewing sarcoma cells and SK-N-AS neuroblastoma cells are moderate expressers of endosialin, and SJSA-1 osteosarcoma cells express very high levels of endosialin. To determine whether endosialin expression was maintained in vivo, A-673 Ewing sarcoma, SK-N-AS neuroblastoma, and SJSA-1 osteosarcoma cells were grown as xenograft tumors in nude mice. The SK-N-AS neuroblastoma and the A-673 Ewing sarcoma lines were selected for in vivo efficacy testing of the anti-endosialin-MC-VC-PABC-MMAE conjugate. The treatment groups included a vehicle control, unconjugated anti-endosialin, an admix control consisting of anti-endosialin and a dose of free MMAE equivalent to the dose administered as the ADC, and the antiendosialin-MC-VC-PABC-MMAE conjugate. The unconjugated anti-endosialin had no antitumor activity and resulted in similar tumor growth as the vehicle control. The admix control produced a modest tumor growth delay. Administration of the anti-endosialin-MC-VC-PABC-MMAE conjugate resulted in a marked prolonged tumor response of both xenograts. These proof-of-concept results break new ground and open a promising drug discovery approach to these rare and neglected tumors.

A phase 1 and randomized controlled phase 2 trial of the safety and efficacy of the combination of gemcitabine and docetaxel with ontuxizumab (MORAb‐004) in metastatic soft‐tissue sarcomas

“…Because endosialin is highly expressed in sarcomas, ontuxizumab could be used to target sarcoma cells and deliver cytotoxic agents linked to it. In a human endosialin‐positive sarcoma xenograft model, prolonged antitumor activity of an anti‐endosialin antibody conjugated to cytotoxic agents was observed in comparison with controls …”

“…In a human endosialin-positive sarcoma xenograft model, prolonged antitumor activity of an anti-endosialin antibody conjugated to cytotoxic agents was observed in comparison with controls. 18 FUNDING SUPPORT…”

Endosialin: molecular and functional links to tumor angiogenesis

“…All these complex molecular relationships of endosialin and its expression in both physiological and pathological conditions call for very careful design of strategies of its diagnostic and therapeutic targeting. Recent studies propose several approaches including tumor immune-PET applications [50], endosialin-specific DNA vaccination targeting tumor vascula- ture [51], and cytotoxic immunotherapy with anti-endosialin humanized antibody ontuxizumab (MORAb-004) or with antibody-drug conjugate [52,53]. Although the efforts towards clinical applications are only in the early stage of pre-clinical and/or clinical development, they show promising results with preliminary observations of antitumor activity, good safety profile and pharmacokinetics [54].…”

Endosialin-Expressing Pericytes Promote Metastatic Dissemination

“…Importantly, resting mesenchymal cells in the healthy adult have low or undetectable levels of endosialin expression. Expression is essentially restricted to activated cells of the mesenchymal lineage during embryogenesis (10,14) as well as during pathologic states including tumor progression and metastasis (13,15,16), making endosialin an oncofetal protein with potential as a biomarker and a therapeutic target (17)(18)(19)(20). In fact, clinical trials in solid tumors and lymphomas with an endosialin-targeting antibody are ongoing (www.clinicaltrials.…”