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Development of a Novel Antibody–Drug Conjugate for the Potential Treatment of Ovarian, Lung, and Renal Cell Carcinoma Expressing TIM-1 Lawrence J

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Development of a Novel Antibody–Drug Conjugate for the Potential Treatment of Ovarian, Lung, and Renal Cell Carcinoma Expressing TIM-1 Lawrence J Published OnlineFirst September 26, 2016; DOI: 10.1158/1535-7163.MCT-16-0393 Large Molecule Therapeutics Molecular Cancer Therapeutics Development of a Novel Antibody–Drug Conjugate for the Potential Treatment of Ovarian, Lung, and Renal Cell Carcinoma Expressing TIM-1 Lawrence J. Thomas1, Laura Vitale2, Thomas O'Neill2, Ree Y. Dolnick3, Paul K. Wallace3, Hans Minderman3, Lauren E. Gergel1, Eric M. Forsberg1, James M. Boyer1, James R. Storey1, Catherine D. Pilsmaker1, Russell A. Hammond1, Jenifer Widger2, Karuna Sundarapandiyan2, Andrea Crocker2, Henry C. Marsh Jr1, and Tibor Keler2 Abstract T-cell immunoglobulin and mucin domain 1 (TIM-1) is a type I copy revealed the antibody was rapidly internalized by cells transmembrane protein that was originally described as kidney in vitro, and internalization was confirmed by quantitative imag- injury molecule 1 (KIM-1) due to its elevated expression in kidney ing flow cytometry. An antibody–drug conjugate (ADC) was and urine after renal injury. TIM-1 expression is also upregulated produced with the anti-TIM-1 antibody covalently linked to the in several human cancers, most notably in renal and ovarian potent cytotoxin, monomethyl auristatin E (MMAE), and desig- carcinomas, but has very restricted expression in healthy tissues, nated CDX-014. The ADC was shown to exhibit in vitro cytostatic thus representing a promising target for antibody-mediated ther- or cytotoxic activity against a variety of TIM-1–expressing cell apy. To this end, we have developed a fully human monoclonal lines, but not on TIM-1–negative cell lines. Using the Caki-1, IgG1 antibody specific for the extracellular domain of TIM-1. This IGROV-1, and A549 xenograft mouse models, CDX-014 showed antibody was shown to bind purified recombinant chimeric significant antitumor activity in a clinically relevant dose range. TIM-1-Fc protein and TIM-1 expressed on a variety of transformed Safety evaluation in nonhuman primates has demonstrated a cell lines, including Caki-1 (human renal clear cell carcinoma), good profile and led to the initiation of clinical studies IGROV-1 (human ovarian adenocarcinoma), and A549 (human of CDX-014 in renal cell carcinoma and potentially other TIM- lung carcinoma). Internalization studies using confocal micros- 1–expressing tumors. Mol Cancer Ther; 15(12); 2946–54. Ó2016 AACR. Introduction functional on regulatory B cells and dendritic cells in mice (5–7). However, the effects of TIM-1 on immune responses remain T-cell immunoglobulin and mucin domain–containing pro- unclear, sometimes contradictory, and potentially dependent on tein 1 (TIM-1) is a type I transmembrane-containing glycoprotein the specificity and affinity of the various agonist and antagonist with an IgV-set domain and a mucin domain with O-linked antibodies and soluble TIM-1 proteins used in these studies (8). glycosylation. TIM-1 has been separately discovered and investi- The TIM-1 glycoprotein was reported to be human hepatitis A gated from three different perspectives. TIM-1 can be expressed on virus cellular receptor-1 (HAVcr-1; ref. 9), and a polymorphism in activated T cells, preferentially on Th2 cells, where costimulation TIM-1 is associated with susceptibility to severe hepatitis A virus with T-cell receptor activation led to T-cell proliferation and IL4 infection in humans (10). TIM-1 was also identified as a receptor production and played an immunoregulatory role in atopy in for Ebola virus and Marburg virus on certain epithelial cells with mouse studies (1). In addition, TIM-1 expression on human T evidence of specific binding to the viral glycoprotein of Ebola virus cells is associated with the regulation of immune responses (2). (11), although subsequent evidence implicated phosphatidylser- TIM-4 expressed on antigen-presenting cells (3) and phosphati- ine binding in the attachment and entry of these and other dylserine (4) have been reported as ligands for TIM-1 that poten- enveloped viruses (12). At this time, it appears multiple mechan- tially mediate these activities. TIM-1 has also been reported to be isms may contribute to the role of TIM-1 in virus entry into cells. The TIM-1 glycoprotein has also been described as kidney injury molecule-1 (KIM-1), which is absent in normal kidney 1Celldex Therapeutics, Inc., Needham, Massachusetts. 2Celldex Ther- and urine but upregulated on proximal tubular epithelial cells and 3 apeutics, Inc., Hampton, New Jersey. Flow and Image Cytometry shed into urine in various renal injuries, including postischemic Facility, Roswell Park Cancer Institute, Buffalo, New York. injury, nephrotoxicant renal injury, including drug-related toxi- Note: Supplementary data for this article are available at Molecular Cancer cities, acute tubular necrosis, diabetic nephropathy, IgA nephrop- Therapeutics Online (http://mct.aacrjournals.org/). athy, membranoproliferative glomerulonephritis, systemic lupus Corresponding Author: Lawrence J. Thomas, Celldex Therapeutics, Inc., 119 erythematosus, polycystic kidney disease, acute and chronic allo- Fourth Ave., Needham, MA 02494. Phone: 781-433-3163; Fax: 781-433-0480; graft rejection, and others (13, 14). TIM-1 has been shown to be a E-mail: [email protected] biomarker for human and animal renal proximal tubule injury doi: 10.1158/1535-7163.MCT-16-0393 (15), and because the ectodomain of TIM-1 is shed into the urine Ó2016 American Association for Cancer Research. following proximal tubule injury, the molecule has found favor as 2946 Mol Cancer Ther; 15(12) December 2016 Downloaded from mct.aacrjournals.org on October 1, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst September 26, 2016; DOI: 10.1158/1535-7163.MCT-16-0393 TIM-1–Targeted ADC for Cancer Therapy a biomarker of renal injury in many species. As a phosphatidyl- Generation of the IgG1 version of mAb 2.70.2 and manufacture serine receptor, TIM-1 has been reported to mediate phagocytosis of the ADC of apoptotic cells by injured kidney epithelial cells (4). Chronic From the panel of human anti-TIM-1 mAbs generated, the mAb conditional expression of TIM-1 in mouse renal epithelial cells clone 2.70.2 was chosen for further development, sequenced, and was shown to cause spontaneous and progressive kidney inflam- an IgG1k mAb was generated. The variable light and heavy chain mation with fibrosis, analogous to progressive kidney disease in regions from anti-TIM-1 mAb clone 2.70.2 were synthesized humans (16). On the other hand, using mice expressing TIM-1 (GenScript) with appropriate restriction sites for cloning into mutants that lack the mucin domain and thus exhibiting impaired expression vectors pEE12.4 and pEE6.4 (Lonza, GS System). The phagocytosis, it was shown that phagocytosis mediated by TIM-1 variable light chain was cloned, in frame, into expression vector actually reduced acute kidney injury (17). pEE12.4 containing the human kappa light chain constant region TIM-1 expression is upregulated in several human cancers, and the variable heavy chain was cloned, in frame, into expression most notably in renal cell carcinoma (RCC), including metastatic vector pEE6.4 containing the human IgG1 heavy chain constant RCC, and ovarian clear cell carcinoma (15, 18). Furthermore, region. Unique restriction sites present in each expression vector TIM-1 expression is associated with a more malignant phenotype (Not I and Pvu I) were utilized to clone the light chain and heavy of RCC, and shedding of the ectodomain has been associated with chain expressing operons and create a double gene expression tumor progression (19, 20). Overexpression of TIM-1 in clear cell vector. A fully human IgG1 antibody was prepared using this RCC (ccRCC) lines activated the IL6/STAT-3/HIF-1A pathway expression vector and designated CDX-014 mAb. apparently dependent on TIM-1 shedding, and phosphorylation The CDX-014 mAb intermediate (2.70.2 IgG1k, also referred to of serine 727 of STAT-3 in ccRCC patients was correlated with as CR014), used for the manufacture of the ADC, was produced by clinical outcome (21). Celldex under GMPs. CDX-014 mAb was expressed in recombi- Expression of TIM-1 in nonmalignant tissues appears quite nant Chinese hamster ovary cells (clone 6F2) and purified using limited in humans. Expression of TIM-1 has been reported on standard methods. The CDX-014 ADC drug substance (or simply activated human T cells (2, 22), as well as on the apical surface of "CDX-014") was manufactured by Lonza AG under GMPs trachea and the basal layer of cornea and conjunctiva (11). TIM-1 as follows. The sulfhydryl-reactive maleimidolcaproyl-valine-cit- shedding and expression on proximal tubular epithelial cells rulline-p-aminobenzyloxycarbonyl-monomethyl auristatin E associated with various types of kidney injury, along with its (mc-vcMMAE; CAS number 646502-53-6) drug cross-linker com- absence in healthy renal tissues, is currently perhaps the most fully bination was manufactured by chemical synthesis by SAFC. The characterized expression of the human protein in nonmalignant CDX-014 mAb was partially reduced with tris-(2-carboxyethyl- tissues. Thus, TIM-1 may serve as an attractive target for antibody- phosphine) hydrochloride, followed by reaction with mc- mediated therapy in certain cancers. vcMMAE to yield the ADC. The drug-to-antibody (DAR) molar In recent years, antibody–drug conjugates (ADCs) have been ratio was approximately 4.5. validated as a valuable drug class with the recent approvals of trastuzumab emtansine (Genentech) for HER2-positive breast Cell lines cancer and brentuximab vedotin (Seattle Genetics) for Hodgkin Caki-1 (ATCC HTB-46, received 2010; human renal clear cell lymphoma. To potentially exploit the strong association of carcinoma), SK-MEL-2 (ATCC HTB-68, received 2010; human TIM-1 expression with certain clear cell carcinomas and other melanoma), and A549 (ATCC CRM-CCL-185, received 2013; malignancies, we have constructed an ADC using a fully human human lung carcinoma) cells were obtained from the ATCC.
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