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1.
Neoplasia ; 23(2): 210-221, 2021 02.
Article in English | MEDLINE | ID: mdl-33385970

ABSTRACT

With the recent approval of 3 new antibody drug conjugates (ADCs) for solid tumors, this class of drugs is gaining momentum for the targeted treatment of cancer. Despite significant investment, there are still fundamental issues that are incompletely understood. Three of the recently approved ADCs contain payloads exhibiting bystander effects, where the payload can diffuse out of a targeted cell into adjacent cells. These effects are often studied using a mosaic of antigen positive and negative cells. However, the distance these payloads can diffuse in tumor tissue while maintaining a lethal concentration is unclear. Computational studies suggest bystander effects partially compensate for ADC heterogeneity in tumors in addition to targeting antigen negative cells. However, this type of study is challenging to conduct experimentally due to the low concentrations of extremely potent payloads. In this work, we use a series of 3-dimensional cell culture and primary human tumor xenograft studies to directly track fluorescently labeled ADCs and indirectly follow the payload via an established pharmacodynamic marker (γH2A. X). Using TAK-164, an anti-GCC ADC undergoing clinical evaluation, we show that the lipophilic DNA-alkylating payload, DGN549, penetrates beyond the cell targeted layer in GCC-positive tumor spheroids and primary human tumor xenograft models. The penetration distance is similar to model predictions, where the lipophilicity results in moderate tissue penetration, thereby balancing improved tissue penetration with sufficient cellular uptake to avoid significant washout. These results aid in mechanistic understanding of the interplay between antigen heterogeneity, bystander effects, and heterogeneous delivery of ADCs in the tumor microenvironment to design clinically effective therapeutics.


Subject(s)
Antineoplastic Agents, Immunological/pharmacokinetics , Bystander Effect/drug effects , Immunoconjugates/pharmacokinetics , Animals , Biomarkers , Cell Line, Tumor , Disease Models, Animal , Drug Monitoring/methods , Female , Fluorescent Antibody Technique , Humans , Immunoglobulin Fc Fragments/metabolism , Mice , Mice, Transgenic , Tumor Microenvironment/drug effects , Xenograft Model Antitumor Assays
2.
Mol Cancer Ther ; 19(10): 2079-2088, 2020 10.
Article in English | MEDLINE | ID: mdl-32788205

ABSTRACT

Guanylyl cyclase C (GCC) is a unique therapeutic target with expression restricted to the apical side of epithelial cell tight junctions thought to be only accessible by intravenously administered agents on malignant tissues where GCC expression is aberrant. In this study, we sought to evaluate the therapeutic potential of a second-generation investigational antibody-dug conjugate (ADC), TAK-164, comprised of a human anti-GCC mAb conjugated via a peptide linker to the highly cytotoxic DNA alkylator, DGN549. The in vitro binding, payload release, and in vitro activity of TAK-164 was characterized motivating in vivo evaluation. The efficacy of TAK-164 and the relationship to exposure, pharmacodynamic marker activation, and biodistribution was evaluated in xenograft models and primary human tumor xenograft (PHTX) models. We demonstrate TAK-164 selectively binds to, is internalized by, and has potent cytotoxic effects against GCC-expressing cells in vitro A single intravenous administration of TAK-164 (0.76 mg/kg) resulted in significant growth rate inhibition in PHTX models of metastatic colorectal cancer. Furthermore, imaging studies characterized TAK-164 uptake and activity and showed positive relationships between GCC expression and tumor uptake which correlated with antitumor activity. Collectively, our data suggest that TAK-164 is highly active in multiple GCC-positive tumors including those refractory to TAK-264, a GCC-targeted auristatin ADC. A strong relationship between uptake of 89Zr-labeled TAK-164, levels of GCC expression and, most notably, response to TAK-164 therapy in GCC-expressing xenografts and PHTX models. These data supported the clinical development of TAK-164 as part of a first-in-human clinical trial (NCT03449030).


Subject(s)
Immunoconjugates/therapeutic use , Animals , Female , HEK293 Cells , Humans , Immunoconjugates/pharmacology , Mice , Mice, Nude , Tissue Distribution , Xenograft Model Antitumor Assays
3.
ACS Med Chem Lett ; 10(8): 1193-1197, 2019 Aug 08.
Article in English | MEDLINE | ID: mdl-31413805

ABSTRACT

Antibody-drug conjugates (ADCs) that incorporate potent indolinobenzodiazepine DNA alkylators as the payload component are currently undergoing clinical evaluation. In one ADC design, the payload molecules are linked to the antibody through a peptidase-labile l-Ala-l-Ala linker. In order to determine the role of amino acid stereochemistry on antitumor activity and tolerability, we incorporated l- and d-alanyl groups in the dipeptide, synthesized all four diastereomers, and prepared and tested the corresponding ADCs. Results of our preclinical evaluation showed that the l-Ala-l-Ala configuration provided the ADC with the highest therapeutic index (antitumor activity vs toxicity).

4.
Haematologica ; 104(8): 1633-1639, 2019 08.
Article in English | MEDLINE | ID: mdl-30733273

ABSTRACT

Antibody-drug conjugates (ADC) are a novel way to deliver potent cytotoxic compounds to cells expressing a specific antigen. Four ADC targeting CD19, including SAR3419 (coltuximab ravtansine), have entered clinical development. Here, we present huB4-DGN462, a novel ADC based on the SAR3419 anti-CD19 antibody linked via sulfo-SPDB to the potent DNA-alkylating agent DGN462. huB4-DGN462 had improved in vitro anti-proliferative and cytotoxic activity compared to SAR3419 across multiple B-cell lymphoma and human acute lymphoblastic leukemia cell lines. In vivo experiments using lymphoma xenografts models confirmed the in vitro data. The response of B-cell lymphoma lines to huB4-DGN462 was not correlated with CD19 expression, the presence of BCL2 or MYC translocations, TP53 inactivation or lymphoma histology. In conclusion, huB4-DGN462 is an attractive candidate for clinical investigation in patients with B-cell malignancies.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Antigens, CD19/metabolism , Antineoplastic Agents/pharmacology , Immunoconjugates/pharmacology , Leukemia/metabolism , Lymphoma/metabolism , Maytansine/analogs & derivatives , Animals , Antibodies, Monoclonal, Humanized/chemistry , Antineoplastic Agents/chemistry , Cell Line, Tumor , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Humans , Immunoconjugates/chemistry , Leukemia/drug therapy , Leukemia/pathology , Lymphoma/drug therapy , Lymphoma/pathology , Maytansine/chemistry , Maytansine/pharmacology , Mice , Treatment Outcome , Xenograft Model Antitumor Assays
5.
Mol Cancer Ther ; 17(6): 1271-1279, 2018 06.
Article in English | MEDLINE | ID: mdl-29588393

ABSTRACT

The myeloid differentiation antigen CD33 has long been exploited as a target for antibody-based therapeutic approaches in acute myeloid leukemia (AML). Validation of this strategy was provided with the approval of the CD33-targeting antibody-drug conjugate (ADC) gemtuzumab ozogamicin in 2000; the clinical utility of this agent, however, has been hampered by safety concerns. Thus, the full potential of CD33-directed therapy in AML remains to be realized, and considerable interest exists in the design and development of more effective ADCs that confer high therapeutic indices and favorable tolerability profiles. Here, we describe the preclinical characterization of a novel CD33-targeting ADC, IMGN779, which utilizes a unique DNA-alkylating payload to achieve potent antitumor effects with good tolerability. The payload, DGN462, is prototypical of a novel class of purpose-created indolinobenzodiazeprine pseudodimers, termed IGNs. With low picomolar potency, IMGN779 reduced viability in a panel of AML cell lines in vitro Mechanistically, the cytotoxic activity of IMGN779 involved DNA damage, cell-cycle arrest, and apoptosis consistent with the mode of action of DGN462. Moreover, IMGN779 was highly active against patient-derived AML cells, including those with adverse molecular abnormalities, and sensitivity correlated to CD33 expression levels. In vivo, IMGN779 displayed robust antitumor efficacy in multiple AML xenograft and disseminated disease models, as evidenced by durable tumor regressions and prolonged survival. Taken together, these findings identify IMGN779 as a promising new candidate for evaluation as a novel therapeutic in AML. Mol Cancer Ther; 17(6); 1271-9. ©2018 AACR.


Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Antineoplastic Agents, Immunological/pharmacology , Immunoconjugates/pharmacology , Sialic Acid Binding Ig-like Lectin 3/antagonists & inhibitors , Animals , Antineoplastic Agents, Alkylating/chemistry , Antineoplastic Agents, Immunological/chemistry , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cytotoxicity, Immunologic , DNA Damage/drug effects , Disease Models, Animal , Drug Design , Humans , Immunoconjugates/chemistry , Leukemia, Myeloid, Acute/drug therapy , Mice , Molecular Structure , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/immunology , Neoplastic Stem Cells/metabolism , Xenograft Model Antitumor Assays
6.
Mol Cancer Ther ; 17(3): 650-660, 2018 03.
Article in English | MEDLINE | ID: mdl-29440292

ABSTRACT

Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here, we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC. ADCs containing the DNA alkylator displayed similar in vitro potency, but improved bystander killing and in vivo efficacy, compared with those of the cross-linker. Thus, the improved in vivo tolerability and antitumor activity achieved in rodent models with ADCs of the novel DNA alkylator could provide an efficacious, yet safer option for cancer treatment. Mol Cancer Ther; 17(3); 650-60. ©2018 AACR.


Subject(s)
Immunoconjugates/pharmacology , Intercalating Agents/pharmacology , Neoplasms/drug therapy , Therapeutic Index, Drug , Xenograft Model Antitumor Assays , Animals , Antineoplastic Agents, Alkylating/chemistry , Antineoplastic Agents, Alkylating/metabolism , Antineoplastic Agents, Alkylating/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Cross-Linking Reagents/chemistry , DNA/genetics , DNA/metabolism , Drug Design , Humans , Immunoconjugates/chemistry , Immunoconjugates/metabolism , Intercalating Agents/chemistry , Intercalating Agents/metabolism , Mice , Neoplasms/pathology , Tumor Burden/drug effects
7.
Neoplasia ; 19(9): 661-671, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28753442

ABSTRACT

Naratuximab emtansine (IMGN529) is an investigational antibody-drug conjugate consisting of a CD37-targeting antibody conjugated to the maytansine-derived microtuble disruptor, DM1. IMGN529 has shown promising preclinical and clinical activity in non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL). Due to the aggressive nature of the disease, DLBCL is often treated with combination therapies to maximize clinical outcomes; therefore, we investigated the potential of combining IMGN529 with both standard-of-care and emerging therapies against multiple oncology-relevant targets and pathways. The strongest enhancement in potency was seen with anti-CD20 antibodies, including rituximab. The combination of IMGN529 and rituximab was more potent than either agent alone, and this combinatorial benefit was associated with increased apoptotic induction and cell death. Additional studies revealed that rituximab treatment increased the internalization and degradation of the CD37-targeting antibody moiety of IMGN529. The combination of IMGN529 and rituximab was highly efficacious in multiple xenograft models, with superior antitumor efficacy seen compared to either agent alone or treatment with R-CHOP therapy. These findings suggest a novel mechanism whereby the potency of IMGN529 can be enhanced by CD20 binding, which results in the increased internalization and degradation of IMGN529 leading to the generation of greater amounts of cytotoxic catabolite. Overall, these data provide a biological rationale for the enhanced activity of IMGN529 in combination with rituximab and support the ongoing clinical evaluation of IMGN529 in combination with rituximab in patients with relapsed and/or refractory DLBCL.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Lymphoma, Non-Hodgkin/drug therapy , Rituximab/pharmacology , Animals , Antibody-Dependent Cell Cytotoxicity/drug effects , Antibody-Dependent Cell Cytotoxicity/immunology , Cell Line, Tumor , Disease Models, Animal , Drug Synergism , Female , Humans , Lymphoma, Non-Hodgkin/immunology , Lymphoma, Non-Hodgkin/metabolism , Lymphoma, Non-Hodgkin/pathology , Mice , Molecular Targeted Therapy , Proteolysis , Xenograft Model Antitumor Assays
8.
Mol Cancer Ther ; 15(6): 1311-20, 2016 06.
Article in English | MEDLINE | ID: mdl-27197308

ABSTRACT

A triglycyl peptide linker (CX) was designed for use in antibody -: drug conjugates (ADC), aiming to provide efficient release and lysosomal efflux of cytotoxic catabolites within targeted cancer cells. ADCs comprising anti-epithelial cell adhesion molecule (anti-EpCAM) and anti-EGFR antibodies with maytansinoid payloads were prepared using CX or a noncleavable SMCC linker (CX and SMCC ADCs). The in vitro cytotoxic activities of CX and SMCC ADCs were similar for several cancer cell lines; however, the CX ADC was more active (5-100-fold lower IC50) than the SMCC ADC in other cell lines, including a multidrug-resistant line. Both CX and SMCC ADCs showed comparable MTDs and pharmacokinetics in CD-1 mice. In Calu-3 tumor xenografts, antitumor efficacy was observed with the anti-EpCAM CX ADC at a 5-fold lower dose than the corresponding SMCC ADC in vivo Similarly, the anti-EGFR CX ADC showed improved antitumor activity over the respective SMCC conjugate in HSC-2 and H1975 tumor models; however, both exhibited similar activity against FaDu xenografts. Mechanistically, in contrast with the charged lysine-linked catabolite of SMCC ADC, a significant fraction of the carboxylic acid catabolite of CX ADC could be uncharged in the acidic lysosomes, and thus diffuse out readily into the cytosol. Upon release from tumor cells, CX catabolites are charged at extracellular pH and do not penetrate and kill neighboring cells, similar to the SMCC catabolite. Overall, these data suggest that CX represents a promising linker option for the development of ADCs with improved therapeutic properties. Mol Cancer Ther; 15(6); 1311-20. ©2016 AACR.


Subject(s)
Epithelial Cell Adhesion Molecule/antagonists & inhibitors , ErbB Receptors/antagonists & inhibitors , Immunoconjugates/administration & dosage , Maytansine/chemistry , Neoplasms/drug therapy , Peptides/chemical synthesis , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Immunoconjugates/chemistry , Immunoconjugates/pharmacokinetics , Immunoconjugates/pharmacology , Maximum Tolerated Dose , Mice , Mice, SCID , Peptides/chemistry , Peptides/pharmacokinetics , Xenograft Model Antitumor Assays
9.
Pharm Res ; 32(11): 3593-603, 2015 Nov.
Article in English | MEDLINE | ID: mdl-25630819

ABSTRACT

PURPOSE: Many antibody-drug conjugates (ADCs) become active only after antigen-mediated internalization and release of the cytotoxic agent via antibody degradation. Quantifying these processes can provide critical information on the suitability of a particular receptor target or antibody for ADC therapy by providing insight into the amount of cytotoxic agent released. We describe a simple and inexpensive radiolabel assay to monitor this process in cultured cancer cells. METHODS: Monoclonal antibodies were trace-labeled at their lysine residues by treatment with the N-hydroxysuccinimide ester of [(3)H]propionic acid. Human cancer cell cultures were treated with the labeled antibody at concentrations sufficient to saturate the targeted antigen. After washing to remove unbound antibody, cells were incubated and analyzed for antigen expression, conjugate degradation and catabolite formation. Results were compared with data obtained from similar assays run with radiolabeled antibody-[(3)H]maytansinoid conjugates ([(3)H]AMCs). To exemplify the method, studies were conducted with a panel of [(3)H]propionamide-antibodies to evaluate processing efficiency in EGFR-expressing SCCHN cell lines, and in NHL cell lines expressing the B-cell targets CD19, CD20, CD22 and CD37. RESULTS: Use of the [(3)H]propionamide-antibody assay yielded cell-mediated processing results similar to those obtained with corresponding maytansinoid ADCs. Further exploration allowed comparison of expression levels, antigen-dependent degradation, and catabolite formation across a panel of EGFR-expressing SCCHN cell lines, and for multiple targets in various B-cell cancer indications. CONCLUSIONS: The [(3)H]propionamide-antibody assay described here is a sensitive, facile method which enables rapid and robust assessment of relative antibody processing amounts for target, antibody, and cell line evaluation.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Immunoconjugates/pharmacology , Maytansine/analogs & derivatives , Maytansine/pharmacology , Molecular Targeted Therapy , Antibodies, Monoclonal, Humanized/chemistry , Cell Line, Tumor , Humans , Immunoconjugates/chemistry , Maytansine/chemistry , Radioligand Assay , Tritium
10.
Blood ; 122(20): 3500-10, 2013 Nov 14.
Article in English | MEDLINE | ID: mdl-24002446

ABSTRACT

CD37 has gathered renewed interest as a therapeutic target in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL); however, CD37-directed antibody-drug conjugates (ADCs) have not been explored. Here, we identified a novel anti-CD37 antibody, K7153A, with potent in vitro activity against B-cell lines through multiple mechanisms including apoptosis induction, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity. The antibody was conjugated to the maytansinoid, DM1, a potent antimicrotubule agent, via the thioether linker, N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and the resulting ADC, IMGN529, retained the intrinsic antibody activities and showed enhanced cytotoxic activity from targeted payload delivery. In lymphoma cell lines, IMGN529 induced G2/M cell cycle arrest after internalization and lysosomal processing to lysine-N(ε)-SMCC-DM1 as the sole intracellular maytansinoid metabolite. IMGN529 was highly active against subcutaneous B-cell tumor xenografts in severe combined immunodeficient mice with comparable or better activity than rituximab, a combination of cyclophosphamide, vincristine, and prednisone, or bendamustine. In human blood cells, CD37 is expressed in B cells at similar levels as CD20, and IMGN529 resulted in potent and specific depletion of normal and CLL B cells. These results support evaluation of the CD37-targeted ADC, IMGN529, in clinical trials in patients with B-cell malignancies including NHL and CLL.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antigens, Neoplasm/immunology , B-Lymphocytes/drug effects , Immunotoxins/therapeutic use , Maytansine/analogs & derivatives , Molecular Targeted Therapy , Tetraspanins/immunology , Animals , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antibodies, Monoclonal, Murine-Derived/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , B-Lymphocytes/pathology , Bendamustine Hydrochloride , Cell Line, Tumor/drug effects , Cyclophosphamide/administration & dosage , Cytotoxicity, Immunologic/drug effects , Drug Screening Assays, Antitumor , Female , Humans , Immunotoxins/immunology , Immunotoxins/pharmacology , Maytansine/administration & dosage , Maytansine/pharmacology , Maytansine/therapeutic use , Mice , Mice, SCID , Nitrogen Mustard Compounds/therapeutic use , Prednisone/administration & dosage , Rituximab , Vincristine/administration & dosage , Xenograft Model Antitumor Assays
11.
Bioconjug Chem ; 22(4): 717-27, 2011 Apr 20.
Article in English | MEDLINE | ID: mdl-21425776

ABSTRACT

In this report, we describe the synthesis of a panel of disulfide-linked huC242 (anti-CanAg) antibody maytansinoid conjugates (AMCs), which have varying levels of steric hindrance around the disulfide bond, in order to investigate the relationship between stability to reduction of the disulfide linker and antitumor activity of the conjugate in vivo. The conjugates were first tested for stability to reduction by dithiothreitol in vitro and for plasma stability in CD1 mice. It was found that the conjugates having the more sterically hindered disulfide linkages were more stable to reductive cleavage of the maytansinoid in both settings. When the panel of conjugates was tested for in vivo efficacy in two human colon cancer xenograft models in SCID mice, it was found that the conjugate with intermediate disulfide bond stability having two methyl groups on the maytansinoid side of the disulfide bond and no methyl groups on the linker side of the disulfide bond (huC242-SPDB-DM4) displayed the best efficacy. The ranking of in vivo efficacies of the conjugates was not predicted by their in vitro potencies, since all conjugates were highly active in vitro, including a huC242-SMCC-DM1 conjugate with a noncleavable linkage which showed only marginal activity in vivo. These data suggest that factors in addition to intrinsic conjugate potency and conjugate half-life in plasma influence the magnitude of antitumor activity observed for an AMC in vivo. We provide evidence that bystander killing of neighboring nontargeted tumor cells by diffusible cytotoxic metabolites produced from target cell processing of disulfide-linked antibody-maytansinoid conjugates may be one additional factor contributing to the activity of these conjugates in vivo.


Subject(s)
Antibodies/chemistry , Antineoplastic Agents/chemistry , Carbon/chemistry , Colonic Neoplasms/drug therapy , Disulfides/chemistry , Maytansine/chemistry , Animals , Antibodies/blood , Antibodies/pharmacology , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacology , Colonic Neoplasms/metabolism , Disulfides/blood , Disulfides/pharmacology , Humans , Maytansine/blood , Maytansine/pharmacology , Mice , Mice, Inbred Strains , Mice, SCID , Molecular Conformation , Xenograft Model Antitumor Assays
12.
Cancer Res ; 70(6): 2528-37, 2010 Mar 15.
Article in English | MEDLINE | ID: mdl-20197459

ABSTRACT

Conjugation of cytotoxic compounds to antibodies that bind to cancer-specific antigens makes these drugs selective in killing cancer cells. However, many of the compounds used in such antibody-drug conjugates (ADC) are substrates for the multidrug transporter MDR1. To evade the MDR1-mediated resistance, we conjugated the highly cytotoxic maytansinoid DM1 to antibodies via the maleimidyl-based hydrophilic linker PEG(4)Mal. Following uptake into target cells, conjugates made with the PEG(4)Mal linker were processed to a cytotoxic metabolite that was retained by MDR1-expressing cells better than a metabolite of similar conjugates prepared with the nonpolar linker N-succinimidyl-4-(maleimidomethyl)cyclohexane-1-carboxylate (SMCC). In accord, PEG(4)Mal-linked conjugates were more potent in killing MDR1-expressing cells in culture. In addition, PEG(4)Mal-linked conjugates were markedly more effective in eradicating MDR1-expressing human xenograft tumors than SMCC-linked conjugates while being tolerated similarly, thus showing an improved therapeutic index. This study points the way to the development of ADCs that bypass multidrug resistance.


Subject(s)
Immunotoxins/pharmacology , Maytansine/analogs & derivatives , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Adenocarcinoma/drug therapy , Adenocarcinoma/metabolism , Animals , Antigens, Neoplasm/chemistry , Antigens, Neoplasm/immunology , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/metabolism , Cell Adhesion Molecules/chemistry , Cell Adhesion Molecules/immunology , Cell Line, Tumor , Colonic Neoplasms/drug therapy , Colonic Neoplasms/metabolism , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Epithelial Cell Adhesion Molecule , Female , Humans , Immunotoxins/chemistry , Immunotoxins/pharmacokinetics , Kidney Neoplasms/drug therapy , Kidney Neoplasms/metabolism , Maleimides/chemistry , Maytansine/chemistry , Maytansine/pharmacokinetics , Maytansine/pharmacology , Mice , Mice, SCID , Polyethylene Glycols/chemistry
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