Chemistry Reference
In-Depth Information
relapse after a complete response (CR) lasting an average of 15 months. Patients
with refractory or relapsed disease have a poor prognosis, with only 30-35%
achieving a second CR with follow-up chemotherapy with a median duration of
relapse-free survival of only 3-12 months. For the 90-95% who do not have
sustained disease-free survival from chemotherapy, the only choice is myelo-
ablative therapy followed by hematopoietic stem cell transplantation (HSCT),
although most patients over 55 do not qualify. Long-term survival for patients
undergoing HSCT is 10-40%, with younger patients performing better.
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5.2 The CD33 Antigen
The earliest hematopoietic cells are CD34 positive and CD33 negative. When
the lymphoid and the myeloid lineages diverge, the differentiating myeloid cells
are CD33 positive. Although mature myeloid cells have only low levels, this
antigen is used as one of the markers of AML, with over 90% of patients being
positive. CD33, also known as Siglec-3, is a 67 kDa, type-1 transmembrane
member of the immunoglobulin family that may be involved in cell adhesion
and/or immune signaling.
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CD33 is an internalizing antigen,
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which is essential for an antibody drug
conjugate (ADC), as conjugates that are not internalized rarely show significant
potency. It is also readily accessible from circulation, making this indication an
ideal proving ground for ADCs. It was hypothesized that a properly con-
structed conjugate would rapidly target and eliminate the AML cells and lar-
gely spare most other normal cells. Differentiating CD33-positive myeloid cells
would also be targeted and eliminated, but the CD34-positive pluripotent stem
cells would likely be spared to a significant extent and repopulate the bone
marrow faster than after traditional chemotherapy, which does not inherently
spare CD34-positive cells. If accomplished, this would result in a therapy for
AML that would be applicable to the patients too sick to take traditional
chemotherapy and may give a treatment that is superior for all patients.
To make such a conjugate, an antibody is required that is selective for CD33.
It should be of the IgG class and it should be chemically well-behaved, meaning
that it is not prone to aggregation or denaturization and that it is readily
amenable to chemical modification. It should ideally also be humanized, but
could be initially examined as a murine antibody, the only kind readily avail-
able at the time this research was initiated. An ideal candidate was found in the
murine anti-CD33 antibody of Bernstein et al.
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5.3 The Calicheamicins
The calicheamicins are a family of natural products isolated fromMicromonospora
echinospora,ssp.calichensis.
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They consist of an enediyne headpiece and a mod-
ified carbohydrate tail consisting of four sugar units and an unusually substituted
aromatic ring (Figure 5.1). The carbohydrate tail exists naturally in a somewhat
helical conformation in solution and fits neatly into the minor groove of DNA.
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