New anti-lung-cancer antibody cluster 12 reacts with human folate receptors present on adenocarcinoma

Franklin, Wilbur A.; Waintrub, Mauricio; Edwards, Dean P.; Christensen, Kurt D.; Prendegrast, Paul; Woods, Jan E.; Bunn, Paul A.; Kolhouse, S. Fred

doi:10.1002/ijc.2910570719

Cited by 108 publications

(79 citation statements)

References 17 publications

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“…To identify maytansinoid catabolites of IMGN853 formed within FRa-positive cancer cells, KB cells were treated with 3 [H]-IMGN853 for 30 minutes, and 3 [H]-labeled metabolites were analyzed after 22-hour incubation in 3 [H]-IMGN853-free medium by HPLC and liquid scintillation counting. The detailed protocol was reported previously (35).…”

Section: Imgn853 Processingmentioning

confidence: 99%

“…The detailed protocol was reported previously (35). To analyze IMGN853 processing by various FRa-positive cell lines, cells were exposed to 25 nmol/L (a saturating concentration) of 3 [H]-IMGN853 or 3 [H]-M9346A for 30 minutes at 37 C, washed in PBS to remove any unbound antibody or conjugate, resuspended in fresh culture medium, and incubated at 37 C in a humidified 6% CO 2 atmosphere for 22 hours. The amount of protein-free radioactivity (processed antibody) and protein-associated radioactivity (unprocessed antibody) was assessed following acetone extraction and liquid scintillation counting, and the data were used to calculate the antibody-binding sites per cell (ABC), % processed antibody, and pmol processed antibody (see the detailed description in Supplementary Methods).…”

Section: Imgn853 Processingmentioning

confidence: 99%

“…After removal from donor mice, tumors were cut into fragments (4-5 mm diameter) and transplanted into recipient mice. After tumor size reached about 110 mm 3 , mice received a single intravenous injection of a maytansinoid conjugate or PBS. Tumor dimensions were measured twice weekly and volume was calculated as (A Â B 2 ) Â 0.5, where A represents the largest and B the perpendicular tumor diameter.…”

Section: In Vivo Efficacymentioning

confidence: 99%

“…Most normal tissues do not express FRa, and transport of physiologic folates into most cells is thought to be mediated by several other proteins, most notably, reduced folate carrier (2). High levels of FRa have been found in serous and endometrioid epithelial ovarian cancer, endometrial adenocarcinoma, and non-small cell lung cancer of the adenocarcinoma subtype (3)(4)(5)(6)(7)(8). Importantly, FRa expression is maintained in metastatic foci and recurrent carcinomas in ovarian cancer patients (9), and after chemotherapy in epithelial ovarian and endometrial cancers (10).…”

Section: Introductionmentioning

confidence: 99%

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IMGN853, a Folate Receptor-α (FRα)–Targeting Antibody–Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRα-Expressing Tumors

Whiteman

Bartle

et al. 2015

Molecular Cancer Therapeutics

177

141

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A majority of ovarian and non-small cell lung adenocarcinoma cancers overexpress folate receptor a (FRa). Here, we report the development of an anti-FRa antibody-drug conjugate (ADC), consisting of a FRa-binding antibody attached to a highly potent maytansinoid that induces cell-cycle arrest and cell death by targeting microtubules. From screening a large panel of anti-FRa monoclonal antibodies, we selected the humanized antibody M9346A as the best antibody for targeted delivery of a maytansinoid payload into FRa-positive cells. We compared M9346A conjugates with various linker/maytansinoid combinations, and found that a conjugate, now denoted as IMGN853, with the N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB) linker and N

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Section: Imgn853 Processingmentioning

confidence: 99%

Section: Imgn853 Processingmentioning

confidence: 99%

Section: In Vivo Efficacymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

IMGN853, a Folate Receptor-α (FRα)–Targeting Antibody–Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRα-Expressing Tumors

Whiteman

Bartle

et al. 2015

Molecular Cancer Therapeutics

177

141

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“…15 Clones were selected by radioimmunoassay for the ability to bind 125 I-labeled folic acid complexed to purified folate receptor and were subsequently characterized using Western blot, immunohistochemistry and flow cytometry.…”

Section: Folate Receptor Antibodymentioning

confidence: 99%

Folate receptor overexpression is associated with poor outcome in breast cancer

Hartmann

Keeney

Lingle

et al. 2007

Intl Journal of Cancer

223

136

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The high affinity folate receptor is a membrane-associated glycoprotein that is preferentially expressed in cancers of epithelial origin and rarely expressed in normal cells. We examined its expression pattern in breast cancer, utilizing a tissue microarray containing samples from 63 invasive breast cancers from women with divergent clinical outcomes. Thirty-three women comprised the poor outcome group with a median time to recurrence of 1.9 years. Thirty women, the good outcome group, were free of recurrence for a minimum of 7 years after diagnosis. The intensity of folate receptor staining was strongly correlated with outcome. There were two summary categories of staining intensity: weak (n 5 42) or strong (n 5 21). In the strong staining group, 17 of 21 women (81%) have recurred and their median survival is 2.4 years. In the weak staining group, 16 of 42 women (38%) have recurred. Their median survival is not estimable. After adjustment for tumor size, nodal status, ER status, adjuvant therapy, histology and tumor grade, strong staining for the folate receptor remained significantly associated with poor outcome, p < 0.001. Our work requires validation in a larger cohort, but supports the possibility of using folate receptor-targeted approaches in the management of breast cancer. ' 2007 Wiley-Liss, Inc.Key words: folate receptor; breast cancer; prognosis Folic acid and its reduced congeners are required for one carbon transfer reactions that are used in the biosynthesis of nucleotide bases, amino acids and other methylated compounds, and consequently, they are needed in larger quantities by proliferating cells. Physiological folates are transported into cells by either a low affinity reduced folate carrier (K m 5 10 25 M) or a high affinity folate receptor (K d 5 10 210 M). [1][2][3][4][5] The reduced folate carrier is ubiquitously expressed and constitutes the sole folate uptake pathway for most normal cells.The high affinity receptor is a glycosylphosphatidylinositolanchored membrane protein originally identified as a mAb-defined antigen in placenta and trophoblastic cells. It is rarely expressed or inaccessible in most normal cells. However, it is upregulated in select cancers of epithelial origin. 6 Distribution and binding studies of the high affinity folate receptor have shown high expression in the majority of ovarian cancers, and lesser degrees of positivity in kidney, breast, uterine and lung cancers. 6-10 Studies in ovarian cancer have shown an association between folate receptor overexpression and tumor aggressiveness. 7,[11][12][13] Studies of folate receptor expression in breast cancers have found varying results, depending on the techniques used and tissues analyzed. Ross et al. measured mRNA for the folate receptor and found levels to be elevated in five cancers when compared with normal breast specimens; however, the degree of elevation was 10-fold less than that seen in ovarian cancer. 10 Garin-Chesa et al. used a mouse monoclonal antibody LK26 to assess folate receptor expression in a variet...

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Folate‐maytansinoids: Target‐selective drugs of low molecular weight

Ladino

Chari

Bourret

et al. 1997

Intl Journal of Cancer

109

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Folate receptor is over‐expressed in a variety of carcinomas. To design a cytotoxic drug that would selectively target these carcinomas, we synthesized folate‐maytansinoids. These drugs showed high affinity toward folate receptor, appeared to enter cells exclusively via the folate receptor–mediated caveolar pathway and displayed high cytotoxic potency (in the range of 10−11 to 10−10 M) and remarkable selectivity for folate receptor–expressing carcinoma cell lines. Folate‐maytansinoids represent a new class of tumor‐specific agents in which the targeting and the cytotoxic function can be altered independently. Int. J. Cancer 73:859–864, 1997. © 1997 Wiley‐Liss, Inc.

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New anti-lung-cancer antibody cluster 12 reacts with human folate receptors present on adenocarcinoma

Abstract: o 1994 Wiley-Liss, Inc.

Cited by 108 publications

References 17 publications

IMGN853, a Folate Receptor-α (FRα)–Targeting Antibody–Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRα-Expressing Tumors

IMGN853, a Folate Receptor-α (FRα)–Targeting Antibody–Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRα-Expressing Tumors

Folate receptor overexpression is associated with poor outcome in breast cancer

Folate‐maytansinoids: Target‐selective drugs of low molecular weight

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