Author: Cavallo, Federica ; Riccardo, Federica ; Arigoni, Maddalena ; Morello, Emanuela ; Tarone, Lidia ; Ferrone, Soldano ; Gattino, Francesca ; Iussich, Selina ; Buracco, Paolo ; Martano, Marina ; Giacobino, Davide ; Maria, Raffaella De ; Sammartano, Federica

Background: Osteosarcoma (OSA) is a highly metastatic pediatric bone tumor. Adjuvant chemotherapy and surgical resection represent standard treatments; however, the prognosis is still poor. Effective strategies are urgently needed. Chondroitin sulfate proteoglycan (CSPG)4 is a transmembrane proteoglycan with a low expression in normal tissues but high expression in several solid tumors, where it plays a central tumorigenic role. Therefore, it represents a promising therapeutic target. The high homology between human and canine CSPG4 and the recognized translational power of canine tumors as preclinical models for human malignancies prompted us to evaluate CSPG4 expression and the consequences of its immune-targeting for both human and canine OSA treatment. Methods: We analyzed CSPG4 overexpression in human and canine OSA samples and its significance for the survival of OSA patients. We exploited functional in vitro experiments to assess the antitumor potential of CSPG4 immune-targeting. Results: CSPG4 is overexpressed in OSA and has possible clinical implications as suggested by an evident correlation between CSPG4 overexpression and a shorter survival for both OSA-affected humans and dogs. The potential of CSPG4 immune-targeting for OSA treatment came from the ability of anti-CSPG4 monoclonal antibodies and sera, derived from human-CSPG4-DNA vaccinated canine patients, to significantly inhibit human and canine CSPG4-positive OSA cell proliferation, migration, and osteospheres generation. Moreover, CSPG4 immune-targeting has been shown to potentiate the effect of doxorubicin. Conclusions: Overall, these results provide the rationale to investigate the CSPG4 immune-targeting as a promising weapon for the treatment of CSPG4-positive OSA canine patients, to be successfully translated to a human setting.

CancersQ2 · MEDICINE

A Novel Antibody-Drug Conjugate (ADC) Delivering a DNA Mono-Alkylating Payload to Chondroitin Sulfate Proteoglycan (CSPG4)-Expressing Melanoma

Q2 · MEDICINE

ArticleOA

Author: Hoffmann, Ricarda M ; Chui, Connie K ; Jackson, Paul J M ; Lacy, Katie E ; Sachouli, Eirini ; Thurston, David E ; Andriollo, Paolo ; Karagiannis, Sophia N ; Spicer, James F ; Mele, Silvia ; Crescioli, Silvia ; Cheung, Anthony

Despite emerging targeted and immunotherapy treatments, no monoclonal antibodies or antibody-drug conjugates (ADCs) directly targeting tumor cells are currently approved for melanoma therapy. The tumor-associated antigen chondroitin sulphate proteoglycan 4 (CSPG4), a neural crest glycoprotein over-expressed on 70% of melanomas, contributes to proliferative signaling pathways, but despite highly tumor-selective expression it has not yet been targeted using ADCs. We developed a novel ADC comprising an anti-CSPG4 antibody linked to a DNA minor groove-binding agent belonging to the novel pyrridinobenzodiazepine (PDD) class. Unlike conventional DNA-interactive pyrrolobenzodiazepine (PBD) dimer payloads that cross-link DNA, PDD-based payloads are mono-alkylating agents but have similar efficacy and substantially enhanced tolerability profiles compared to PBD-based cross-linkers. We investigated the anti-tumor activity and safety of the anti-CSPG4-(PDD) ADC in vitro and in human melanoma xenografts. Anti-CSPG4-(PDD) inhibited CSPG4-expressing melanoma cell growth and colony formation and triggered apoptosis in vitro at low nanomolar to picomolar concentrations without off-target Fab-mediated or Fc-mediated toxicity. Anti-CSPG4-(PDD) restricted xenograft growth in vivo at 2 mg/kg doses. One 5 mg/kg injection triggered tumor regression in the absence of overt toxic effects or of acquired residual tumor cell resistance. This anti-CSPG4-(PDD) can deliver a highly cytotoxic DNA mono-alkylating payload to CSPG4-expressing tumors at doses tolerated in vivo.

Frontiers in ImmunologyQ2 · MEDICINE

Chondroitin Sulfate Proteoglycan 4 and Its Potential As an Antibody Immunotherapy Target across Different Tumor Types

Q2 · MEDICINE

ReviewOA

Author: Tsoka, Sophia ; Griffin, Merope ; Karagiannis, Sophia N ; Chiaruttini, Giulia ; Nakamura, Mano ; Spicer, James F ; Ilieva, Kristina M ; Tutt, Andrew N J ; Crescioli, Silvia ; Lacy, Katie E ; Cheung, Anthony ; Mele, Silvia

Overexpression of the chondroitin sulfate proteoglycan 4 (CSPG4) has been associated with the pathology of multiple types of such as melanoma, breast cancer, squamous cell carcinoma, mesothelioma, neuroblastoma, adult and pediatric sarcomas, and some hematological cancers. CSPG4 has been reported to exhibit a role in the growth and survival as well as in the spreading and metastasis of tumor cells. CSPG4 is overexpressed in several malignant diseases, while it is thought to have restricted and low expression in normal tissues. Thus, CSPG4 has become the target of numerous anticancer treatment approaches, including monoclonal antibody-based therapies. This study reviews key potential anti-CSPG4 antibody and immune-based therapies and examines their direct antiproliferative/metastatic and immune activating mechanisms of action.

100 Deals associated with Anti-CSPG4-IL2 (Provenance)

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Indication	Highest Phase	Country/Location	Organization	Date
Ganglioneuroblastoma	Preclinical	US	Provenance Biopharmaceuticals Corp.	-
Melanoma	Preclinical	US	Provenance Biopharmaceuticals Corp.	-
Prostatic Cancer	Preclinical	US	Provenance Biopharmaceuticals Corp.	-

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