Disclosed are anti-CD45 antibodies, antigen binding fragments thereof, and antibody drug conjugates (ADCs) that specifically bind to human CD45. Such antibodies and ADCs are useful in therapeutic methods, including methods of depleting CD45+ cells from a patient. The compositions and methods described herein can be used to treat a disorder directly, for instance, by depleting a population of CD45+ cancer cells or autoimmune cells. The compositions and methods described herein can also be used to prepare a patient for hematopoietic stem cell transplant therapy, and to improve the engraftment of hematopoietic stem cell transplants, by selectively depleting endogenous CD45+ cells prior to the transplant procedure.