# IMMUNOTOXINS IN HUMAN BONE MARROW TRANSPLANTATION

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 1992 · $173,657

## Abstract

Immunotoxins (IT) are a new class of pharmacologic agent consisting of
monoclonal antibodies (mAb) linked to potent catalytic toxins such as ricin
toxin A chain (RTA).  While efficacy of IT has been observed, toxic side
effects have limited the efficacy in established animal models and in
clinical trials.  Theoretically, IT should provide specific target cell
elimination since the mAb portion is directed against a specific epitope
and is required for the internalization of the toxin moiety which by itself
can not efficiently internalize.  Therefore, it is somewhat surprising that
these reagents do not have a higher therapeutic index in vivo.  The goal of
this proposal is to perform a comprehensive, well-controlled study dealing
with IT toxicity in order to understand the mechanisms involved with the
impaired efficacy in vivo, and then, to design second and third generation
IT which bypass these toxicity mechanisms.  We have chosen to focus this
proposal on anti-Ly1-RTA since anti-Ly1 recognizes the murine homologue of
human CD5.  Anti-human CD5-RTA is now in clinical trials for graft-versus-
host-disease (GVHD) treatment.  We will test the hypothesis that different
regions of the IT molecule are responsible for different IT toxicities.  We
will focus on the most problematic IT toxicities including hepatic,
vascular, and renal toxicities and we will determine the contribution of
antibody activation to IT toxicity.  Since the major interest of our group
is the application of IT to the field of bone marrow transplantation, we
will test the previously unexplored hypothesis that irradiation enhances in
vivo anti-Ly1-RTA toxicity.  We will analyze the relative contribution of
the recipient's microenvironment as compared to lymphohematopoietic system
by using non-transplanted or irradiated and syngeneically transplanted
congeneic mice which differ in Ly1 alleleic determinants.  Once we have
established a relationship between certain regions of the IT molecule and
toxicity, we will investigate modifications chosen on the basis of their
ability to reduce toxicity related to the toxin or antibody moeity of IT.
We will test the hypothesis that removal of sugars from RTA will reduce IT
toxicity.  We will test the hypothesis that toxicities can be further
reduced by the removal of the Fc region of the mAb.  If these modifications
can reduce toxicity without sacrificing IT activity, we will test modified
anti-Ly1-RTA for efficacy in our established GVHD model which has proven to
be limited by the toxicity of unmodified anti-Ly1-RTA in past published
studies.  These studies should provide valuable insights into the clinical
toxicities observed with current IT usage.

## Key facts

- **NIH application ID:** 3174307
- **Project number:** 2R01CA036725-09A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **SAM.gov UEI:** KABJZBBJ4B54
- **Principal Investigator:** Daniel A Vallera
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $173,657
- **Award type:** 2
- **Project period:** 1984-01-01 → 1997-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3174307

## Citation

> US National Institutes of Health, RePORTER application 3174307, IMMUNOTOXINS IN HUMAN BONE MARROW TRANSPLANTATION (2R01CA036725-09A1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3174307. Licensed CC0.

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