Strongly Enhanced Antitumor Activity of Trastuzumab and Pertuzumab Combination Treatment on HER2-Positive Human Xenograft Tumor Models

Scheuer, Werner; Friess, Thomas; Burtscher, Helmut; Bossenmaier, Birgit; Endl, Josef; Hasmann, Max

doi:10.1158/0008-5472.can-08-4597

Cited by 533 publications

(398 citation statements)

References 41 publications

Supporting

Mentioning

381

Contrasting

Unclassified

Order By: Relevance

“…This has been shown to be responsible for different effects on signaling in both tumor and cardiac cells (23). On the basis of these observations, we can speculate that the combination of Erb-hcAb with the other antibodies targeting different epitopes of ErbB2 could lead to synergistic or additive effects on prostate tumor cells as previously shown for breast tumor cells (37,38).…”

Section: Discussionsupporting

confidence: 54%

Effects of a human compact anti-ErbB2 antibody on prostate cancer

et al. 2012

View full text Add to dashboard Cite

Abstract. Prostate cancer is the most commonly diagnosed malignancy in men in developed countries. ErbB2, a tyrosine kinase receptor overexpressed in many human cancer types, contributes to prostate cancer progression by activating the androgen receptor in a steroid poor environment, thus promoting androgen-independent cell growth. The consequent development of hormone refractory tumors is a major obstacle in prostate cancer therapy. The inhibition of ErbB2 signal transduction pathways by the use of human antibodies could be a valuable alternative strategy for cancer therapy. We performed a comparative analysis in vitro and in vivo of the antitumor effects of three different antibodies targeting different epitopes of ErbB2: Herceptin (trastuzumab), 2C4 (pertuzumab) and Erb-hcAb (human anti-ErbB2-compact antibody), a novel fully human compact antibody produced in our laboratory. Herein, we demonstrate that the growth of both androgen-dependent and independent prostate cancer cells was efficiently inhibited by Erb-hcAb. The antitumor effects induced by Erb-hcAb on some cell lines were more potent than those observed for either Herceptin or 2C4. Thus, Erb-hcAb could be a promising candidate in the immunotherapy of prostate cancer for which no obvious treatment has been reported so far.

show abstract

Section: Discussionsupporting

confidence: 54%

Effects of a human compact anti-ErbB2 antibody on prostate cancer

et al. 2012

View full text Add to dashboard Cite

show abstract

“…little information on the action or interaction of these agents in ovarian cancer, even though they have shown promise for some patients in the clinic (19,20,24). When combined, trastuzumab and pertuzumab show an enhanced antitumor activity in ovarian cancer xenografts, as they do in breast (38,39) and non-small-cell lung cancer xenografts (39 molecular phenotype and therefore responsiveness to other therapies. ERa was upregulated in response to treatment with trastuzumab (alone or in combination with pertuzumab) but not pertuzumab alone.…”

Section: Discussionmentioning

confidence: 99%

Trastuzumab and Pertuzumab Produce Changes in Morphology and Estrogen Receptor Signaling in Ovarian Cancer Xenografts Revealing New Treatment Strategies

Faratian

Zweemer

Nagumo

et al. 2011

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: The aim of this study was to investigate the antitumor effects of HER2-directed combination therapy in ovarian cancer xenograft models to evaluate their potential. The combinations of trastuzumab and pertuzumab, and trastuzumab and aromatase inhibitor therapy were investigated.Experimental Design: The effects of trastuzumab, pertuzumab, and letrozole on growth response, apoptosis, morphology, and gene and protein expression were evaluated in the SKOV3 ovarian cancer cell line xenograft and a panel of five human ovarian xenografts derived directly from clinical specimens.Results: The combination of HER2-directed antibodies showed enhanced antitumor activity compared with single antibody therapy in the SKOV3 xenograft model. Apoptosis, morphology, and estrogenregulated gene expression were modulated by these antibodies in both spatial and temporal manners. A panel of ovarian cancer xenografts showed differential growth responses to the combination of trastuzumab and pertuzumab. High HER2 expression and increasing HER3 protein expression on treatment were associated with growth response. In trastuzumab-treated SKOV3 tumors, there was a change in tumor morphology, with a reduction in frequency of estrogen receptor alpha (ERa)-negative clear cell areas. Trastuzumab, but not pertuzumab, increased expression of ERa in SKOV3 xenografts when analyzed by quantitative immunofluorescence. ERa and downstream signaling targets were modulated by trastuzumab alone and in combination. Trastuzumab enhanced the responsiveness of SKOV3 xenografts to letrozole when given in combination.Conclusions: These data suggest that trastuzumab in combination with pertuzumab could be an effective approach in high HER2-expressing ovarian cancers and could also enhance sensitivity to endocrine therapy in ERa-positive ovarian cancer. Clin Cancer Res; 17(13); 4451-61. Ó2011 AACR.

show abstract

“…8 Their mechanisms of action are complementary, providing broader blockade of the HER2-positive tumor cell proliferation and survival signaling. 9 The CLEOPATRA clinical trial showed that patients with metastatic HER2-positive breast cancer treated with combination of pertuzumab and trastuzumab plus docetaxel significantly prolonged progression-free survival, 10 and simultaneous blockade of HER2 by trastuzumab and pertuzumab may overcome trastuzumab-resistance.…”

Section: Introductionmentioning

confidence: 99%

Structural and functional characterization of MBS301, an afucosylated bispecific anti-HER2 antibody

Huang

Liu

et al. 2018

mAbs

View full text Add to dashboard Cite

MBS301, a glyco-engineered bispecific anti-human epidermal growth factor receptor 2 (HER2) antibody with a typical IgG1 monoclonal antibody structure, was developed through dual-cell expression and in vitro assembling process. MBS301 consists of two half antibodies engineered from trastuzumab and pertuzumab, respectively. Integrity and purity profiles of MB301 indicated that the heterodimerization of the two half antibodies was successful. The high and similar melting temperatures (Tm1,72.0°C and Tm2, 84.8°C) of MBS301 compared with those of its parental monoclonal antibodies trastuzumab and pertuzumab (in-house made T-mab and P-mab, respectively) revealed its structural compactness. With computer-modeling experiments and Biacore binding and competition kinetics studies, the binding stoichiometry between MBS301 and HER2-ECD was determined to be 1:1 and the two arms of MBS301 were shown to bind to domains II and IV of HER2-ECD antigen simultaneously. MBS301 displayed synergistic bioactivities as the combination of T-mab and P-mab in vitro in multiple cancer cell lines and in vivo in xenograft mouse model studies, and showed more effective activity than T-mab or P-mab used individually. Moreover, fucose-knockout dramatically increased MBS301’s binding affinity to low affinity FcγRIIIa allotype 158F (KD = 2.35 × 10−7M) to near the high affinity level of allotype V158 (KD = 1.17 × 10−7M). This resulted in far more effective ADCC activity of MBS301 than the combination of T-mab and P-mab in killing HER2-positive cancer cells. Hence, a novel fully afucosylated anti-HER2 bispecific antibody with improved antitumor activities was generated and shown to have the potential to be used for treating HER2-positive but trastuzumab-resistant solid tumors.

show abstract

Strongly Enhanced Antitumor Activity of Trastuzumab and Pertuzumab Combination Treatment on HER2-Positive Human Xenograft Tumor Models

Cited by 533 publications

References 41 publications

Effects of a human compact anti-ErbB2 antibody on prostate cancer

Effects of a human compact anti-ErbB2 antibody on prostate cancer

Trastuzumab and Pertuzumab Produce Changes in Morphology and Estrogen Receptor Signaling in Ovarian Cancer Xenografts Revealing New Treatment Strategies

Structural and functional characterization of MBS301, an afucosylated bispecific anti-HER2 antibody

Contact Info

Product

Resources

About