Request for Funding
Medical Student Research Fellowship for Summer 2004
Three different projects are listed below
Mentor: Drs. E. Vitetta, L. Pop and C. Liu
Department: Cancer and Immunology Center
Room number: NB9.210B
Mail Code: 8576
Phone number: 8-1200
E-mail: ellen.vitetta@utsouthwestern.edu, laurentiu.pop@utsouthwestern.edu,
xiaoyun.liu@utsouthwestern.edu
Project title: Evaluating a mouse anti-human CD22 monoclonal antibody which
has been genetically engineered to shorten its short half life in vivo in order
to improve its therapeutic activity as an immunotoxin.
Human subjects IRB approved project number (where applicable):
Animal subjects IRB approved project number APN# 0034-03-22-1:
Project Type (patient-based research, animal-based research, or basic research;
this characterization is only to permit a general classification for grouping
similar types of projects)
Basic Research
Brief Description of Project:
Antibody-based therapeutics have been under development for 30 years. The first antibody for the therapy of cancer was approved by the FDA in 1997. There are currently over 200 antibodies and antibody-based therapeutics being evaluated in clinical trials.
One antibody therapeutic which is under development in our laboratory is an anti-CD22 monoclonal antibody (RFB4) linked to the catalytic A chain of the plant toxin, ricin. This immunotoxin has been evaluated in over 100 patients and it is showing efficacy in both lymphoma and pre-B ALL. However, it does cause a side effect called vascular leak syndrome (VLS). In an effort to eliminate VLS, we have re-engineered the ricin A chain to inactivate the site which initiates VLS. We are currently re-engineering the antibody so that it has a shorter half life in the blood and therefore will be eliminated as quickly as possible after it binds to tumor cells. The combination of these two approaches should yield a more effective and less toxic immunotoxin.
In order to shorten the half life of an antibody, one can either remove its entire Fc portion or re-engineer its Fc portion so that it cannot bind to critical Fc receptors (FcRn) on vascular endothelial cells. The binding of an antibody to these receptors results in a longer half life. One such construct has mutations in amino acids residues at positions 435 and 310. This mutant, chimeric antibody (cRFB4/H435A/H310A) is expected to have a decreased persistence in the circulation. We will use this mutant to prepare and evaluate an immunotoxin.
Mentor: Dr. E. Vitetta and Ms. E. Coleman and K. Brooks
Department: Cancer and Immunology Center
Room number: NB9.210B
Mail Code: 8576
Phone number: 8-1200
E-mail: ellen.vitetta@utsouthwestern.edu, elaine.coleman@utsouthwestern.edu,
kimberly.brooks@utsouthwestern.edu
Project title: Examining UV3-tumor cell line interactions in vitro in order
to understand how the antibody mediates its anti-tumor activity.
Human subjects IRB approved project number (where applicable):
Animal subjects IRB approved project number APN# 0034-03-22-1:
Project Type (patient-based research, animal-based research, or basic research;
this characterization is only to permit a general classification for grouping
similar types of projects)
Basic Research
Brief Description of Project:
I. Background:
We have developed an anti-human CD54 monoclonal antibody which has unusual anti-tumor activity in SCID mice with human myeloma tumors. In this tumor model, the antibody works primarily by inducing antibody dependent cellular cytotoxicity (ADCC) and complement-dependent cytoxicity (CDC). The antibody is highly unusual in its ability to cure early disease and treat advanced disease. The antibody has been chimerized (i.e. made into a semi- "human" antibody) and will enter clinical trials in patients with refractory myeloma.
We have recently shown that this antibody recognizes CD54 on a variety of other human tumors, including lymphoma, breast, prostate, lung, pancreas and melanoma. It has been tested in several of these tumors grown in SCID mice. In some instances it works solely by ADCC and CDC, while in others it has additional anti-tumor activities which have not yet been well defined but probably include anti-growth activity, anti-angiogenic activity, etc.
II. Objective:
The objective of this project is to examine UV3-tumor cell line interactions in vitro in order to understand how the antibody mediates its anti-tumor activity. The first step is to examine the role of effector function, mediated by either CDC or ADCC. In CDC, the complement protein C1q recognizes and attaches to the Fc portion of an antibody bound to the surface of the cell (in this case UV3 bound to a tumor cell). After binding, C1q initiates the complement cascade involving many other complement proteins. The end result is cell lysis. In ADCC, receptors on effector cells specifically recognize the Fc portion of the antibody as their antigen. Once the receptor has bound to the Fc, these cytotoxic effector cells can cause lysis of the antibody-bound cell. The effect of UV3 treatment on tumor cell proliferation and apoptosis will also be examined in an effort to further understand how UV3 mediates its anti-tumor effects.
Project title: Determining abnormalities in normal breast epithelial cells obtained from reductive mammoplasty and in benign breast tumors.
Human subjects IRB approved project number (0896-269 and 1202-700):
Animal subjects IRB approved project number (N/A):
Project Type (patient-based research, animal-based research, or basic research;
this characterization is only to permit a general classification for grouping
similar types of projects)
Basic Research
Brief Description of Project:
Objective: To determine if normal epithelial cells or epithelial cells from benign tumors have extra copies of HER-2 genes or CEP 17 chromosome
Background
HER-2 gene amplification or over expression is a very important prognostic indicator
in breast cancer. At present, the diagnosis is made only on the primary tumor.
Such patients have a very poor prognosis if the tumor recurs. However there
is a very effective treatment for this condition which has very few side effects.
It is a humanized antibody to HER-2 which finds to HER-2 (which is a receptor
for growth factors) and neutralizes its activity. Recently, in our laboratory,
we have found that a high percentage of patients whose primary tumor with HER-2
negative can acquire HER-2 gene amplification as the tumor progresses. Therefore,
this is a very important diagnosis to make in order to obtain appropriate treatment.
One very puzzling fact is that even patients who do not have HER-2 gene amplification
by the conventional method (HER-2 gene copies/CEP 17 copies equals two or more;
the HER-2 gene resides on chromosome 17) frequently have HER-2 gene amplification
and chromosome 17 amplification. The question arises as to whether this portion
of chromosome 17 and chromosome 17 itself are highly susceptible to mutagenesis
and duplication respectively. If we find that there is allover expression of
either the HER-2 gene or CEP 17 in normal epithelial cells or in patients with
benign tumors, it may indicate that these are premalignant lesions and that
the patient should be followed more closely than is conventionally performed.
Previous Research Activities or Publications with Medical Students:
Publications:
Spiridon, C., Guinn, S., and Vitetta E. A comparison of the in vitro and in vivo activities of IgG and F(ab)'2 fragments of a mixture of three anti-Her-2 antibodies. Clinical Cancer Research, in press, 2004.
Medical Students (1999-2003):
Yussein Aguirre
Cameron Aslam
Michelle Crank
Sarah Guinn
Jason Puthottile
Vishal Shah
Don Stone
Previous Research Activities or Publications with Medical Students:
Publications:
1. Vitetta, E.S. Coleman, E., Ghetie, M-A., Ghetie, V., Michalek, J., Pop, L.M., Smallshaw, J.E. and Spiridon, C. Immunotherapy. In: Fundamental Immunology, 5th Edition, ed: W. Paul Lippincott, Williams and Wilkens, New York, Chapter 50, pp-1621-1659,2003.
2. Spiridon, C., Guinn, S., and Vitetta E. A comparison of the in vitro and in vivo activities of IgG and F(ab)'2 fragments of a mixture of three anti-Her-2 antibodies. Clinical Cancer Research, in press, 2004.
Medical Students (1999-2003):
Yussein Aguirre
Abby Albright
Cameron Aslam
Ahmed Attia
Kim Brooks
Elaine Coleman
Michelle Crank
Leslie Greenlee
Sarah Guinn
Chandria Jones
David Kosub
Shilpa Mistry
Jason Puthottile
Vishal Shah
Don Stone
Liz Winger
Lydia Wu
Jian Yao
Michael Yen
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