Phase I Study of Trastuzumab-DM1, an HER2 Antibody-Drug Conjugate, Given Every 3 Weeks to Patients With HER2-Positive Metastatic Breast Cancer

Krop, Ian E.; Beeram, Muralidhar; Modi, Shanu; Jones, Suzanne F.; Holden, Scott N.; Yu, Wei; Girish, Sandhya; Tibbitts, Jay; Yi, Joo‐Hee; Sliwkowski, Mark X.; Jacobson, Fred; Lutzker, Stuart; Burris, Howard A.

doi:10.1200/jco.2009.26.2071

Cited by 532 publications

(437 citation statements)

References 21 publications

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“…In contrast, conjugation to pAcPhe is chemically defined, efficient, and scalable, and the oxime linkage is highly stable, which should also reduce toxicity because of release of the free toxin in vivo. Indeed, although trastuzumab-DM1 has shown efficacy in humans, it has also induced irreversible axonal degradation in nonhuman primates, which may be because of either release of the free toxin or ADC species in the heterogeneous mixture with altered specificities or pharmacology (29). Moreover, maleimide conjugation has been shown to adversely affect the stability of ADCs (20).…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of site-specific antibody-drug conjugates using unnatural amino acids

Axup

Bajjuri²,

Ritland³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

516

454

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Antibody-drug conjugates (ADCs) allow selective targeting of cytotoxic drugs to cancer cells presenting tumor-associated surface markers, thereby minimizing systemic toxicity. Traditionally, the drug is conjugated nonselectively to cysteine or lysine residues in the antibody. However, these strategies often lead to heterogeneous products, which make optimization of the biological, physical, and pharmacological properties of an ADC challenging. Here we demonstrate the use of genetically encoded unnatural amino acids with orthogonal chemical reactivity to synthesize homogeneous ADCs with precise control of conjugation site and stoichiometry. p -Acetylphenylalanine was site-specifically incorporated into an anti-Her2 antibody Fab fragment and full-length IgG in Escherichia coli and mammalian cells, respectively. The mutant protein was selectively and efficiently conjugated to an auristatin derivative through a stable oxime linkage. The resulting conjugates demonstrated excellent pharmacokinetics, potent in vitro cytotoxic activity against Her2 + cancer cells, and complete tumor regression in rodent xenograft treatment models. The synthesis and characterization of homogeneous ADCs with medicinal chemistry-like control over macromolecular structure should facilitate the optimization of ADCs for a host of therapeutic uses.

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Section: Resultsmentioning

confidence: 99%

“…Furthermore, the Her2 receptor shows little normal tissue expression and is known to internalize readily, making it a good candidate for ADC targeting. Indeed, Genentech has nonspecifically conjugated maytansine (DM1) to trastuzumab to produce an ADC that has shown excellent efficacy in preclinical and phase I and II clinical trials (11,29).…”

Section: Resultsmentioning

confidence: 99%

Synthesis of site-specific antibody-drug conjugates using unnatural amino acids

Axup

Bajjuri²,

Ritland³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

516

454

View full text Add to dashboard Cite

show abstract

“…29 To further evaluate the drug distribution, deglycosylated PanP-DM1 was analyzed by ESI-TOF-MS. As illustrated in Fig. 1C, the spectrum shows 8 prominent peaks, which are equally spaced and correspond to antibody linked to zero to 7 DM1 molecules.…”

Section: Characterization Of Panp-dm1mentioning

confidence: 99%

Preclinical studies of a Pro-antibody-drug conjugate designed to selectively target EGFR-overexpressing tumors with improved therapeutic efficacy

Yang¹,

Guo²,

Chen³

et al. 2016

mAbs

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Antibody-drug conjugates (ADCs) have exhibited potent clinical benefits in cancer therapy. However, development of ADCs against epidermal growth factor receptor (EGFR) has limitations because of wide expression of EGFR in both normal and tumor tissues. Previously, we developed an anti-EGFR proteaseactivated antibody (pro-antibody), termed as PanP, which remains inert against EGFR until activated by tumor-specific protease. Herein, we for the first time report a new class of pro-antibody-drug conjugate (PDC) against EGFR, denoted as PanP-DM1. It has been designed to selectively target the EGFRoverexpressing tumor cells and exert greater anti-tumor activity compared with PanP. Our data showed that PanP-DM1 also could be selectively activated by tumor-specific protease 'uPA'. Furthermore, activated PanP-DM1 was potently cytotoxic against EGFR-overexpressing tumor cell lines in vitro. Crucially, our data indicated that PanP-DM1 was significantly more effective in eradicating EGFR-overexpressing tumors in vivo. Additionally, toxicity was preliminarily evaluated in mice as measured by body weight loss. In summary, our study suggests that PanP-DM1, a novel pro-antibody-drug conjugate, has cancer-selectivity, efficacy and safety profile that supports its potential use for EGFR-overexpressing tumors.

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“…This is an antibody drug conjugate comprising trastuzumab and emtansine (DM1), a tubulin polymerization inhibitor. Following successful trials, which showed high efficacy and relatively mild side effects, 46,47 T-DM1 has been approved for the treatment of HER2-positive metastatic breast cancer patients, who previously received trastuzumab and chemotherapy.…”

Section: Targeted Cancer Therapy Directed At the Egfr (Her/ Erbb) Familymentioning

confidence: 99%

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

Gaborit

Lindzen

Yarden

2015

Human Vaccines & Immunotherapeutics

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Cancer progression depends on stepwise accumulation of oncogenic mutations and a select group of growth factors essential for tumor growth, metastasis and angiogenesis. Agents blocking the epidermal growth factor receptor (EGFR, also called HER1 and ERBB1) and the co-receptor called HER2/ERBB2 have been approved over the last decade as anti-cancer drugs. Because the catalytically defective member of the family, HER3/ERBB3, plays critical roles in emergence of resistance of carcinomas to various drugs, current efforts focus on antibodies and other anti-HER3/ERBB3 agents, which we review herein with an emphasis on drug combinations and some unique biochemical features of HER3/ERBB3.

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Phase I Study of Trastuzumab-DM1, an HER2 Antibody-Drug Conjugate, Given Every 3 Weeks to Patients With HER2-Positive Metastatic Breast Cancer

Abstract: At the MTD of 3.6 mg/kg every 3 weeks, T-DM1 was associated with mild, reversible toxicity and substantial clinical activity in a heavily pretreated population. Phase II and III trials in patients with advanced HER2-positive breast cancer are under way.

Cited by 532 publications

References 21 publications

Synthesis of site-specific antibody-drug conjugates using unnatural amino acids

Synthesis of site-specific antibody-drug conjugates using unnatural amino acids

Preclinical studies of a Pro-antibody-drug conjugate designed to selectively target EGFR-overexpressing tumors with improved therapeutic efficacy

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

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