Development of a Novel Antibody-Drug Conjugate for the Potential Treatment of Ovarian, Lung, and Renal Cell Carcinoma Expressing TIM-1.
T-cell immunoglobulin and mucin domain 1 (TIM-1) is a type I transmembrane protein that was originally described as kidney injury molecule 1 (KIM-1) due to its elevated expression in kidney and urine after renal injury. TIM-1 expression is also upregulated in several human cancers, most notably in renal and ovarian carcinomas, but has very restricted expression in healthy tissues, thus representing a promising target for antibody-mediated therapy. To this end, we have developed a fully human monoclonal IgG1 antibody specific for the extracellular domain of TIM-1. This antibody was shown to bind purified recombinant chimeric TIM-1-Fc protein and TIM-1 expressed on a variety of transformed cell lines, including Caki-1 (human renal clear cell carcinoma), IGROV-1 (human ovarian adenocarcinoma), and A549 (human lung carcinoma). Internalization studies using confocal microscopy revealed the antibody was rapidly internalized by cells in vitro, and internalization was confirmed by quantitative imaging flow cytometry. An antibody-drug conjugate (ADC) was produced with the anti-TIM-1 antibody covalently linked to the potent cytotoxin, monomethyl auristatin E (MMAE), and designated CDX-014. The ADC was shown to exhibit in vitro cytostatic or cytotoxic activity against a variety of TIM-1-expressing cell lines, but not on TIM-1-negative cell lines. Using the Caki-1, IGROV-1, and A549 xenograft mouse models, CDX-014 showed significant antitumor activity in a clinically relevant dose range. Safety evaluation in nonhuman primates has demonstrated a good profile and led to the initiation of clinical studies of CDX-014 in renal cell carcinoma and potentially other TIM-1-expressing tumors. Mol Cancer Ther; 15(12); 2946-54. ©2016 AACR.
Celldex Therapeutics, Inc., Needham, Massachusetts. lthomas@celldex.com.
Lawrence J
LJ
Thomas
Celldex Therapeutics, Inc., Hampton, New Jersey.
Laura
L
Vitale
Celldex Therapeutics, Inc., Hampton, New Jersey.
Thomas
T
O'Neill
Flow and Image Cytometry Facility, Roswell Park Cancer Institute, Buffalo, New York.
Ree Y
RY
Dolnick
Flow and Image Cytometry Facility, Roswell Park Cancer Institute, Buffalo, New York.
Paul K
PK
Wallace
Flow and Image Cytometry Facility, Roswell Park Cancer Institute, Buffalo, New York.
Hans
H
Minderman
Celldex Therapeutics, Inc., Needham, Massachusetts.
Lauren E
LE
Gergel
Celldex Therapeutics, Inc., Needham, Massachusetts.
Eric M
EM
Forsberg
Celldex Therapeutics, Inc., Needham, Massachusetts.
James M
JM
Boyer
Celldex Therapeutics, Inc., Needham, Massachusetts.
James R
JR
Storey
Celldex Therapeutics, Inc., Needham, Massachusetts.
Catherine D
CD
Pilsmaker
Celldex Therapeutics, Inc., Needham, Massachusetts.
Russell A
RA
Hammond
Celldex Therapeutics, Inc., Hampton, New Jersey.
Jenifer
J
Widger
Celldex Therapeutics, Inc., Hampton, New Jersey.
Karuna
K
Sundarapandiyan
Celldex Therapeutics, Inc., Hampton, New Jersey.
Andrea
A
Crocker
Celldex Therapeutics, Inc., Needham, Massachusetts.
Henry C
HC
Marsh
Celldex Therapeutics, Inc., Hampton, New Jersey.
Tibor
T
Keler
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D000072596:Hepatitis A Virus Cellular Receptor 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008252:Macaca fascicularis; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D054730:Protein Interaction Domains and Motifs / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000072596:Hepatitis A Virus Cellular Receptor 1; D018796:Immunoconjugates; D007074:Immunoglobulin G