Antibody-drug combo may obviate need for tissue-matching in organ transplant

For those hoping for a new heart, liver, bone marrow or other organ, the wait for a compatible organ has always been part of the excruciating drama of transplantation.

If an organ isn’t tissue-matched — that is, if it doesn’t bear an immunological resemblance to the patient’s own tissue — the patient’s body will likely reject it. Even when the organ is a close match, there are enough differences that the organ recipient will likely have to take anti-rejection drugs, possibly for life. These drugs have toxic side effects and leave patients vulnerable to infections.

All of this may change in the future because of a set of collaborative discoveries by Agnieszka Czechowicz, MD, PhD, assistant professor of pediatrics at the School of Medicine, and her colleagues at Stanford, Harvard, Boston Children’s Hospital and the National Institute of Allergy and Infectious Diseases.

Czechowicz began the work as a graduate student in the laboratory of Irving Weissman, MD, who directs Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. She continued her research during her residency and fellowship at the Dana Farber Cancer Institute/Boston Children’s Cancer and Blood Disorders Center before returning to Stanford as a faculty member.

In a pair of papers published online Feb. 6 in Nature Communications, the researchers describe how an antibody-drug conjugate seeks out and eliminates blood-producing stem cells in mice. This is particularly important because other studies in animals and patients have shown that replacing blood-producing stem cells with a donor's blood-producing cells can promote the immune acceptance of tissues from that donor. Unfortunately, current methods of eliminating blood-producing stem cells rely on toxic levels of chemotherapy or radiation, or both, that not only have acutely damaging and long-lasting side effects, but also leave the recipient vulnerable to infection while the transplanted cells engraft. 

No damaging side effects in mice

In the first study, Czechowicz and her colleagues found that the antibody-drug conjugate could effectively and specifically eliminate blood-producing stem cells in a mouse without damaging side effects. Once eliminated, the researchers could replace the original blood-producing stem cells with others from an immunologically identical donor animal. Czechowicz shares lead authorship of this study with Rahul Palchaudhuri, PhD, a former postdoctoral scholar at Harvard. Derrick Rossi, PhD, associate professor of stem cell and regenerative biology at Harvard, and David Scadden, MD, co-director of the Harvard Stem Cell Institute, are the senior authors.

The study showed that a single dose of the antibody-drug combination could specifically target blood-forming stem cells and kill more than 99 percent of them without harming other sorts of cells. Transplanted cells could then easily take up residence in the bone marrow. The animals’ immune reactions were not significantly affected and could continue to defend against various pathogens during the procedure.

This type of approach would be exciting news for clinicians who currently rely on blood-forming stem cell transplants to cure their patients of a variety of blood and immune disorders, including cancer. It would also be exciting news for researchers developing blood-forming stem cell gene therapies, as this treatment could also enable safe engraftment of gene-modified cells. 

Using nonmatching stem cells

But there’s more. In the second study, the researchers found that this same antibody-drug conjugate, in combination with a short-course of immune suppression, could also be used to replace some of a mouse’s blood-producing stem cells with donor stem cells that do not match those of the recipient. 

“The result is a chimera — a mix of original and transplanted blood stem cells — in the recipient,” Czechowicz said. Mice with these mixed blood and immune cells did not develop any complications and were able to accept a skin transplant from the stem-cell donor even many months later, the researchers found. 

“Using this technique to make recipients tolerant to donor organs is incredibly exciting,” Czechowicz said. “It indicates that we could have a relatively safe method of inducing tolerance without the need for chronic immune suppression, and do that without needing to match donors and recipients for tissue type. This approach could be transformative for the transplant field.” 

Czechowicz shares lead authorship of this second study with Zhanzhuo Li, MD, PhD, a staff scientist at NIAID. Co-senior authors of the paper are Rossi and Philip Murphy, MD, chief of the Laboratory of Molecular Immunology at the institute.

Czechowicz and her colleagues caution that this work has so far only been done in mice and has yet to be proven in clinical trials. However, the work shows that it may be possible to someday safely and easily restore patients’ blood and immune systems with no chemotherapy or radiation, and moreover give patients an organ from a mismatched donor, with minimal immunosuppression.

The first study was supported by the Boston Children’s Hospital Trust, the Jake Wetchler Foundation, the Harvard Blavatnik Biomedical Accelerator Fund, the American Society of Hematology, the National Institutes of Health, the  California Institute for Regenerative Medicine the Gunn/Olivier Research Fund, the Virginia and D.K. Ludwig Fund for Cancer Research, the Stinehart-Reed Foundation, the HL Snyder Medical Foundation, the Leona M. and Harry B. Helmsley Charitable Trust, the New York Stem Cell Foundation, the Harvard Stem Cell Institute and the American Federation for Aging Research.

The second paper was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, the Boston Children’s Hospital Trust, the National Institutes of Health, the Leona M. and Harry B. Helmsley Charitable Trust, the New York Stem Cell Foundation, the Harvard Stem Cell Institute and the American Federation for Aging Research

Stanford’s Department of Pediatrics also supported the work.