title: Crystalline monoclonal antibodies for subcutaneous delivery.
abstract: Therapeutic applications for mAbs have increased dramatically in recent years, but the large quantities required for clinical efficacy have limited the options that might be used for administration and thus have placed certain limitations on the use of these agents. We present an approach that allows for s.c. delivery of a small volume of a highly concentrated form of mAbs. Batch crystallization of three Ab-based therapeutics, rituximab, trastuzumab, and infliximab, provided products in high yield, with no detectable alteration to these proteins and with full retention of their biological activity in vitro. Administration s.c. of a crystalline preparation resulted in a remarkably long pharmacokinetic serum profile and a dose-dependent inhibition of tumor growth in nude mice bearing BT-474 xenografts (human breast cancer cells) in vivo. Overall, this approach of generating high-concentration, low-viscosity crystalline preparations of therapeutic Abs should lead to improved ease of administration and patient compliance, thus providing new opportunities for the biotechnology industry.
authors.affiliation: Altus Biologics, Inc., 625 Putnam Avenue, Cambridge, MA 02139, USA.
authors.forename: Mark X
authors.initials: MX
authors.lastname: Yang
authors.forename: Bhami
authors.initials: B
authors.lastname: Shenoy
authors.forename: Matthew
authors.initials: M
authors.lastname: Disttler
authors.forename: Reena
authors.initials: R
authors.lastname: Patel
authors.forename: Margaret
authors.initials: M
authors.lastname: McGrath
authors.forename: Sergey
authors.initials: S
authors.lastname: Pechenov
authors.forename: Alexey L
authors.initials: AL
authors.lastname: Margolin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000302:isolation & purification* / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000628:therapy; D003238:Connective Tissue / Q000473:pathology; D003460:Crystallization; D005260:Female; D006801:Humans; D000069285:Infliximab; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D051381:Rats; D000069283:Rituximab; D014183:Transplantation, Heterologous; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab; D000069285:Infliximab; D000068878:Trastuzumab