Animal model for toxicology and dose prediction

• US 20040045045A1
• Filed: 05/30/2003
• Published: 03/04/2004
• Est. Priority Date: 05/30/2002
• Status: Abandoned Application

• Current Assignee: MacroGenics, Inc.
• Original Assignee: MacroGenics, Inc.
• Inventors: Young, Peter F., Mather, Jennie P.
• Application Number:
  US10/448,766
• Publication Number:
  US 20040045045A1
• Time in Patent Office: Days
• US Class Current: 800/14
• CPC Class Codes: A01K 2227/10 Mammal
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2227/30 Bird
• CPC Class Codes: A01K 2267/03 Animal model, e.g. for test or diseases
• CPC Class Codes: A01K 67/0271 Chimeric vertebrates, e.g. comprising exogenous cells
• CPC Class Codes: A61K 49/0008 Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure

Abstract

The invention relates to the use of fetal tissues to generate a tissue model in a non-human animal. The tissue model comprises target tissues allowed to progress through development in vivo in a non-human host in order to obtain tissues having a mature phenotype that can be used to assess toxicity and/or efficacy of an agent.

Claims

1. A method for generating a non-human vertebrate animal model having target normal tissue of mature phenotype and target diseased tissues both from a first vertebrate animal, comprising the steps of:

(a) implanting immature target normal tissue or normal tissue recombinants made from immature or progenitor cells of the first animal into a second, non-human vertebrate recipient animal at a location sufficient to support growth and maturation of said tissue;

(b) allowing the target normal tissue of the first animal to develop into a tissue with a mature phenotype;

(c) implanting target diseased tissue or diseased cells of the first animal into a non-human vertebrate recipient animal at a location sufficient to support growth of the diseased tissue; and

(d) allowing the target diseased tissue or diseased cells from the first animal to grow.

2. The method of claim 1, wherein both the target normal tissue and the target diseased tissue from the first animal are implanted into different locations in one single non-human vertebrate animal.

3. The method of claim 1, wherein the normal and the diseased target tissues are implanted into separate animals.

4. The method of claim 1, wherein the donor and the normal and the recipient animals are of different species.

5. The method of claim 1, wherein both the implanted target normal tissue and the implanted target diseased tissue are human in origin.

6. The method of claim 1, wherein the implanted target tissue is derived from a species selected from the following group:

mice, rats, rabbits, birds, cats, dogs, pigs, sheep, goats, deer, horses, cattle, humans, and non-human primates.

7. The method of claim 6, wherein the non-human primate is a baboon, chimpanzee or monkey.

8. The method of claim 1, wherein the non-human vertebrate recipient animal is selected from the group consisting of immunodeficient mice, rats, rabbits, cats, frogs, birds, dogs, pigs, sheep, goats, and non-human primates.

9. The method of claim 8, wherein the animal is an immunodeficient rodents.

10. A tissue model for the evaluation of target tissue from a first vertebrate animal species having mature phenotype present within an immunodeficient, second, non-human recipient or host animal, wherein the target normal and/or diseased first species tissue is selected from the group consisting of tissues of the following biological systems:

Central Nervous System;

Brain—

Cerebrum (gray and white matter containing neurons, glia, etc.) and Brain—

Cerebellum, Eye, Brainstem (pons, medulla, midbrain), Spinal Cord;

Endocrine;

Adrenal (cortex and medulla), Ovary, Pancreas (Islets of Langerhans and exocrine pancreas), Parathyroid, Pituitary (adenohypophysis and neurohypophysis), Testis, Thyroid (follicular epithelium, parafollicular cells, colloid, etc.);

Breast;

Breast (lobules, ducts, myoepithelial cells, etc.);

Hematopoietic;

Spleen, Tonsil, Thymus, Bone marrow (lymphocytes, monocytes/macrophages, granulocytes, erythroid precursors, megakaryocytes, mast cells, osteoclasts, osteoblasts), Peripheral blood cells (neutrophils, lymphocytes, monocytes, basophils, eosinophils, red blood cells, platelets);

Respiratory;

Lung (bronchi, bronchioles, alveoli, etc.);

Cardiovascular;

Heart, Blood vessels (arteries, veins, etc.);

Gastrointestinal;

Esophagus, Stomach (fundus), Small intestine (Ileum, jejunum or duodenum), Colon, Liver (portal triads, hepatic cells, etc.), Salivary Gland;

Genitourinary;

Kidney, Urinary, Bladder, Ureter, Urethra, Fallopian tube, Vagina, Placenta, Prostate, Uterus, Cervix;

Musculoskeletal;

Skeletal muscle;

Skin;

Skin (epidermis, appendages, dermis);

Peripheral Nerve;

Peripheral Nerve;

Mesothelial cells;

Lining cells from chest wall, abdominal wall, pericardium or from the surface of gastrointestinal, heart and/or lung samples, etc.

11. An immunodeficient rodent having human tissue models for target normal human tissue having mature phenotype and diseased human tissue wherein the normal human tissue is selected from the group consisting of lung, prostate, kidney, pancreas, bladder, skin, liver, heart, colon, duodenum, stomach, thyroid, salivary gland, and thymus.

12. A method for assessing the effect of a therapeutic treatment directed against a target diseased tissue, comprising the steps of

(a) applying such treatment to an immunodeficient non-human vertebrate recipient animal of one species that has at least one each of a target normal tissue having mature phenotype and a target diseased tissue from another vertebrate animal species, and

(b) assessing the effect of the treatment on the target normal and diseased tissues.

13. The method of claim 12, wherein the therapeutic treatment is selected from the group consisting of radio-, chemo-, or radiopharmaceutical therapy or radio-immunotherapy.

14. The method of claim 12, wherein the therapeutic treatment comprises the administration of agents useful for radio-imaging of tumors.

15. A method for determining a dose of an agent that is toxic to a target tissue, comprising the steps of:

(a) administering an agent to an immunodeficient recipient animal that has at least one of a target normal tissue having a mature phenotype and a target cancerous tissue from a donor animal, and

(b) assessing for any toxic effects of the agent on the normal and cancerous target tissues.

16. A method for identifying an agent that is toxic to target diseased or cancerous cells to a greater extent than normal cells, comprising the steps of:

(a) administering an agent to an immunodeficient recipient animal that has a target normal tissue having mature phenotype and a diseased or cancerous target tissue from a donor animal, and

(b) identifying the agent that reduces the growth of or destroys the diseased or cancerous target tissues to a greater extent than normal tissues.

17. A method for determining an effective amount of an agent that is toxic to diseased or cancerous cells to a greater extent than normal cells, comprising the steps of:

(a) administering an agent to an immunodeficient recipient animal that has a normal target tissue having mature phenotype and a cancerous human tissue from a donor animal, and

(b) determining an amount of the agent that is effective on the normal and diseased or cancerous target tissues.

18. A whole animal-based screening assay, comprising the use of nonhuman host animals that have already received target tissue implants according to the invention, or parts thereof, for testing the cytotoxic, cytostatic, antimicrobial, anti-inflammatory or other therapeutic properties of treatments administered to said animals, or for testing the activity of such treatments in controlling or inhibiting the development of cancer, infections and/or disease.

19. A method of screening and identifying or testing a treatment, drug or other substance for activity against the development of or in the treatment of cancer, infection and/or disease, comprising the steps of

(a) treating a non-human host animal that has already receive target tissue implants according to the teachings of this invention, or a part thereof, with said treatment, drug or other substance concerned, and

(b) detecting or noting any reduced incidence in the development of cancer, infection and/or disease, and reduction in morbidity, as compared with corresponding animals that are not treated with the treatment, drug or substance, or detecting or noting an effectiveness in maintaining, restoring or improving bodily function.