Improved Lysosomal Trafficking Can Modulate the Potency of Antibody Drug Conjugates.
Antibody drug conjugates (ADCs) provide an efficacious and relatively safe means by which chemotherapeutic agents can be specifically targeted to cancer cells. In addition to the selection of antibody targets, ADCs offer a modular design that allows selection of ADC characteristics through the choice of linker chemistries, toxins, and conjugation sites. Many studies have indicated that release of toxins bound to antibodies via noncleavable linker chemistries relies on the internalization and intracellular trafficking of the ADC. While this can make noncleavable ADCs more stable in the serum, it can also result in lower efficacy when their respective targets are not internalized efficiently or are recycled back to the cell surface following internalization. Here, we show that a lysosomally targeted ADC against the protein APLP2 mediates cell killing, both in vitro and in vivo, more effectively than an ADC against Trop2, a protein with less efficient lysosomal targeting. We also engineered a bispecific ADC with one arm targeting HER2 for the purpose of directing the ADC to tumors, and the other arm targeting APLP2, whose purpose is to direct the ADC to lysosomes for toxin release. This proof-of-concept bispecific ADC demonstrates that this technology can be used to shift the intracellular trafficking of a constitutively recycled target by directing one arm of the antibody against a lysosomally delivered protein. Our data also show limitations of this approach and potential future directions for development.
Rinat Laboratories, Pfizer Inc. , 230 East Grand Avenue, South San Francisco, California 94080, United States.
Rachel M
RM
DeVay
Rinat Laboratories, Pfizer Inc. , 230 East Grand Avenue, South San Francisco, California 94080, United States.
Kathy
K
Delaria
Rinat Laboratories, Pfizer Inc. , 230 East Grand Avenue, South San Francisco, California 94080, United States.
Guoyun
G
Zhu
Rinat Laboratories, Pfizer Inc. , 230 East Grand Avenue, South San Francisco, California 94080, United States.
Charles
C
Holz
Rinat Laboratories, Pfizer Inc. , 230 East Grand Avenue, South San Francisco, California 94080, United States.
Davide
D
Foletti
Rinat Laboratories, Pfizer Inc. , 230 East Grand Avenue, South San Francisco, California 94080, United States.
Janette
J
Sutton
Rinat Laboratories, Pfizer Inc. , 230 East Grand Avenue, South San Francisco, California 94080, United States.
Gary
G
Bolton
Worldwide Medicinal Chemistry, Pfizer Inc. , 445 Eastern Point Road, Groton, Connecticut 06340, United States.
Russell
R
Dushin
Rinat Laboratories, Pfizer Inc. , 230 East Grand Avenue, South San Francisco, California 94080, United States.
Christine
C
Bee
Rinat Laboratories, Pfizer Inc. , 230 East Grand Avenue, South San Francisco, California 94080, United States.
Jaume
J
Pons
Rinat Laboratories, Pfizer Inc. , 230 East Grand Avenue, South San Francisco, California 94080, United States.
Arvind
A
Rajpal
Rinat Laboratories, Pfizer Inc. , 230 East Grand Avenue, South San Francisco, California 94080, United States.
Hong
H
Liang
Rinat Laboratories, Pfizer Inc. , 230 East Grand Avenue, South San Francisco, California 94080, United States.
David
D
Shelton
Rinat Laboratories, Pfizer Inc. , 230 East Grand Avenue, South San Francisco, California 94080, United States.
Shu-Hui
SH
Liu
Rinat Laboratories, Pfizer Inc. , 230 East Grand Avenue, South San Francisco, California 94080, United States.
Pavel
0000-0001-8695-577X
P
Strop
D016564:Amyloid beta-Protein Precursor / Q000276:immunology / Q000627:therapeutic use; D000818:Animals; D018033:Antibodies, Bispecific / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D006801:Humans; D018796:Immunoconjugates / Q000378:metabolism / Q000494:pharmacology*; D008247:Lysosomes / Q000378:metabolism*; D008819:Mice, Nude; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000627:therapeutic use; D057900:Transcytosis
D016564:Amyloid beta-Protein Precursor; D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D009419:Nerve Tissue Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C084104:APLP2 protein, human