Maximizing therapeutic index using fully Fc-silent antibody platform

Antibody drug conjugates (ADCs) have transformed the clinical landscape for the treatment of cancers over the last two decades spear-headed by intensive research of linker and payload chemistries. However, toxicities remain a concern where impairing dosage and administration frequency of the ADCs could impact overall clinical benefit. We developed Stealth-Body (SB) by introducing specific mutations in the Fc region of the antibody to limit Fc-Fcgamma receptor interactions without compromising efficacy and maintaining manufacturing scalability, when compared to LALA mutations, the SB Fc showed improved pharmacokinetic (PK) parameters such as half-life in serum studies in double transgenic mice (huFcRn and hualbumin) and complete loss of binding to all Fcgamma receptors as well as C1q. Based on these characteristics, we are developing a ADCs containing SB Fc for selective anti-tumor efficacy and limiting interaction with Fcgamma receptors to reduce off-target toxicities. Antibodies containing WT Fc and SB Fcs were conjugated with MMAE and efficacy was determined in in vitro and in vivo studies. Currently, PK studies in mice and preliminary toxicology studies in non-human primates are ongoing. To determine whether SB Fc conjugates were able to avoid off-target toxicities, cancer cell lines expressing FcgammaRs were treated with SB Fc containing conjugates or WT Fc conjugates. As expected, the SB Fc conjugates displayed no off-target cell killing toxicities in these cell lines compared to WT Fc conjugates. Conjugates containing the SB Fcs maintained potent efficacy in vitro in cancer cell lines similar WT Fc containing conjugates, indicating that efficacy was not compromised by the mutations in the SB Fc. In in vivo cell line derived xenograft (CDX) models, the SB Fc conjugates showed strong tumor growth inhibition (TGI) as single injection doses and similar potent minimum efficacious dose (MED) was observed in CDX models and determined to be 0.6 mg/kg. These preclinical data demonstrate the potential of SB Fc containing ADCs as promising for the treatment of various cancer indications and supports their use for clinical development.