Building and characterizing antibody-targeted lipidic nanotherapeutics.
Immunoliposomes provide a complementary, and in many instances advantageous, drug delivery strategy to antibody-drug conjugates. Their high carrying capacity of 20,000-150,000 drug molecules/liposome, allows for the use of a significantly broader range of moderate-to-high potency small molecule drugs when compared to the comparably few subnanomolar potency maytansinoid- and auristatin-based immunoconjugates. The multivalent display of 5-100 antibody fragments/liposome results in an avidity effect that can make use of even moderate affinity antibodies, as well as a cross-linking of cell surface receptors to induce the internalization required for intracellular drug release and subsequent activity. The underlying liposomal drug must be effectively engineered for long circulating pharmacokinetics and stable in vivo drug retention in order to allow for the drug to be efficiently delivered to the target tissue and take advantage of the site-specific bioavailability provided for by the targeting arm. In this chapter, we describe the rationale for engineering stable immunoliposome-based therapeutics, methods required for preparation of immunoliposomes, as well as for their physicochemical and in vivo characterization.
Merrimack Pharmaceuticals, Cambridge, Massachusetts, USA.
Dmitri B
DB
Kirpotin
Charles O
CO
Noble
Mark E
ME
Hayes
Zhaohua
Z
Huang
Tad
T
Kornaga
Yu
Y
Zhou
Ulrik B
UB
Nielsen
James D
JD
Marks
Daryl C
DC
Drummond
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000493:pharmacokinetics; D000915:Antibody Affinity; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D004339:Drug Compounding / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods*; D004355:Drug Stability; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008055:Lipids / Q000737:chemistry; D008081:Liposomes / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D050997:Nanomedicine / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D015202:Protein Engineering / Q000379:methods; D051381:Rats; D013439:Sulfhydryl Reagents / Q000737:chemistry
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D007128:Immunoglobulin Fragments; D008055:Lipids; D008081:Liposomes; D013439:Sulfhydryl Reagents; D011092:Polyethylene Glycols