Abstract 5445: Preclinical anti-tumor efficacy of an anti-C4.4a (LYPD3) antibody drug conjugate for the treatment of lung squamous cell carcinoma

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA C4.4a (LYPD3) has been identified previously as a cancer- and metastasis-associated internalizing cell surface protein. Targeting C4.4a with a specific antibody-drug conjugate (ADC) represents an unique opportunity to treat tumors with high unmet medical need such as squamous cell carcinomas SCC, in particular lung SCC. We have generated an anti-C4.4a ADC consisting of a fully human monoclonal antibody linked to a non cell-permeable tubulin-binding auristatin cytotoxic agent (technology licensed from Seattle Genetics). In vitro, anti-C4.4a ADC showed an anti-proliferative efficacy (IC50) in the nanomolar range in cell lines endogenously expressing C4.4a (e.g. human lung cancer cell lines NCI-H292 and NCI-H322). High ADC stability and selectivity was observed in transfected A549 lung cancer cells over-expressing C4.4a compared to mock-transfected cells. In vivo, anti-C4.4a ADC exhibited a potent and selective antitumor activity in various human xenograft models (NCI-H292, NCI-H322, SCC-4) as well as in two SCC (Lu7433, Lu7343) and one pleomorphic (Lu7064) patient-derived lung cancer xenograft models. The in vivo efficacy is strictly target-dependent and selective as no efficacy was observed in C4.4a negative models (Fadu, Lu 7700) or using a non-specific isotype antibody ADC (NCI-H292, NCI-H322). A minimal effective dose (MED) as low as 1.9 mg/kg, response rates of up to 100%, and additive anti-tumor efficacy in combination with cisplatin were observed in the NCI-H292 xenograft model. Furthermore, it has been demonstrated that NCI-H292 were still sensitive to ADC treatment when tumors were allowed to regrow after the initial treatment cycle(). The anti-C4.4a ADC, which is fully cross-reactive with the mouse orthologue of C4.4a, was well tolerated at efficacious doses. Reversible skin reddening was observed only at doses markedly higher than the MED. In summary, anti-C4.4a ADC is a promising therapeutic candidate for the treatment of C4.4a-expressing squamous cell carcinomas, andpreclinical development has been initiated. Citation Format: Joerg Willuda, Lars Linden, Hans-Georg Lerchen, Charlotte Kopitz, Sven Golfier, Ute Bach, Joachim Schumacher, Beatrix Stelte-Ludwig, Oliver Von Ahsen, Claudia Schneider, Frank Dittmer, Rudolf Beier, Sherif El-Sheik, Jan Tebbe, Gabriele Leder, Heiner Apeler, Rolf Jautelat, Bertolt Kreft, Karl Ziegelbauer. Preclinical anti-tumor efficacy of an anti-C4.4a (LYPD3) antibody drug conjugate for the treatment of lung squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5445. doi:10.1158/1538-7445.AM2014-5445