New bispecific antibody targets her2 and CD3 on Tcells producing effective imm respns

[Lani]

ABSTRACT: Phase I Trial of the Trifunctional Anti-HER2 x Anti-CD3 Antibody Ertumaxomab in Metastatic Breast Cancer [Clinical Cancer Research; Subscribe]
Purpose: Ertumaxomab is an intact bispecific antibody targeting HER2/neu and CD3 with selective binding to activatory Fc? type I/III receptors, resulting in the formation of a tri-cell complex between tumor cells, T cells, and accessory cells. Patients with metastatic breast cancer were enrolled into a multicenter phase I dose-escalating trial.

Experimental Design: Three ascending doses of ertumaxomab (10-200 ?g) were administered i.v. on day 1, 7 ± 1, and 13 ± 1. Safety and tolerability were the primary objectives. Secondary objectives were antitumor activity and different immunologic variables.

Results: Fifteen out of 17 enrolled patients completed the study. One hundred micrograms was identified as the maximal tolerable single dose. Most drug-related adverse events were mild and transient including fever (94%), rigors (47%), headache (35%), nausea (29%), vomiting (29%). Grades 3 and 4 (Common Toxicity Criteria) were lymphocytopenia (76%) and elevation of liver enzymes (47%). One patient (200 ?g dose) developed severe hypotension and respiratory distress syndrome, another patient (150 ?g dose) developed a systemic inflammatory response syndrome and acute renal failure. Aggravation of congestive heart failure was seen in one patient with preexisting ventricular dysfunction after administration of the third dose (200 ?g). All adverse events were fully reversible. Antitumor response was seen in 5 out of 15 evaluable patients (one with a complete response, two with partial responses, two with stable disease) at dose levels of ?100 ?g. Measurements of cytokines (interleukin-6, interleukin-2, tumor necrosis factor-?, and IFN-?) suggest a strong T helper cell type 1-associated immune response. The induction of human anti-mouse/anti-rat antibodies was detected in 5 out of 16 (31%) patients.

Discussion: Treatment with triple infusions of ertumaxomab yields a strong immunologic response. Doses up to 100 ?g can be safely infused with close monitoring of patients. The observed clinical responses are encouraging and indicate antitumor efficacy.

[Rich66]

Oct 2008 Charité Campus Benjamin Franklin, Department of Hematology and Oncology, Hindenburgdamm 30/31, D-12200 Berlin, Germany. philipp.kiewe@charite.de


Ertumaxomab is an intact bispecific antibody targeting HER2/neu and CD3 with preferential binding to activating Fcgamma type I/III-receptors, resulting in the formation of a tri-cell complex among tumour cell, T cell and accessory cell. Recently, the antibody demonstrated antitumour efficacy against HER2/neu low-expressing tumours resistant to trastuzumab. Data from a completed Phase I study in metastatic breast cancer patients indicates strong immune responses. Owing to efficient tumour cell destruction by humoral and T-cell-dependent mechanisms, differing from conventional HER2/neu directed treatments, and a potential for long-lasting antitumour immunoreactivity, ertumaxomab is at present investigated within Phase II studies enrolling metastatic breast cancer patients even without HER2/neu gene amplification.

[Rich66]

http://clinicaltrials.gov/ct2/show/N...ns_ex=Y&rank=2

Phase II Study With the Trifunctional Antibody Ertumaxomab to Treat Metastatic Breast Cancer After Progression on Trastuzumab Therapy
This study is currently recruiting participants.
Verified by Fresenius Biotech GmbH, March 2008
Sponsors and Collaborators: Fresenius Biotech GmbH
Fresenius Biotech North America
Information provided by: Fresenius Biotech GmbH ClinicalTrials.gov Identifier: NCT00522457

Purpose This study has the purpose to demonstrate clinical efficacy of the investigational new drug ertumaxomab in patients with HER 2/neu overexpressing (3+ or 2+ with a positive FISH test result) metastatic breast cancer progressing after trastuzumab treatment.
Ertumaxomab is a trifunctional bispecific antibody targeting Her-2/neu on tumor cells and CD3 on T cells. Trifunctional antibodies represent a new concept for targeted anticancer therapy. This new antibody class has the capability to redirect T cells and accessory immune effector cells (e.g. macrophages, dendritic cells [DCs] and natural killer [NK] cells) to the tumor site. According to preclinical data, trifunctional antibodies activate these immune cells, which can trigger a complex anti-tumor immune response.

Condition Intervention Phase Metastatic Breast Cancer
Advanced Breast Cancer
Drug: ertumaxomab
Phase II

Genetics Home Reference related topics: breast cancer
MedlinePlus related topics: Breast Cancer Cancer
Drug Information available for: Immunoglobulins Globulin, Immune Visilizumab Trastuzumab Ertumaxomab
U.S. FDA Resources
Study Type:
Interventional
Study Design:
Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study

Official Title:
Phase II Study Of The Trifunctional Bispecific Anti-HER-2/Neu x Anti-CD3 Antibody Ertumaxomab In Patients With HER-2/Neu Overexpressing (3+ Or 2+/FISH+) Metastatic Breast Cancer Progressing After Trastuzumab Treatment

Further study details as provided by Fresenius Biotech GmbH:

Primary Outcome Measures: Clinical efficacy measured b