Development of a bispecific tetravalent CD33/CD3 TandAbfor the treatment of AML.

Konference: 2015 51th ASCO Annual Meeting - účast ČR

Kategorie: Maligní lymfomy a leukémie

Téma: Poster

Číslo abstraktu: 7071

Autoři: Dr. Uwe Reusch; Kristina Ellwanger; Michael Weichel; Dr. Vera Molkenthin, Ph.D.; Judith A. Fox, Ph.D.; Dr. Stefan Knackmuss; Ivica Fucek; Erich Rajkovic; Eugene Zhukovsky; Jeanmarie Guenot, Ph.D.; Dr. Martin Treder

Background: Acute Myeloid Leukemia (AML) is a hematologic malignancy with dire prognosis; immunotherapy may offer a much needed alternative to cytotoxic chemotherapy. TandAbs are tetravalent, bispecific diabodies that exceed renal clearance limits, providing both avidity and pharmacokinetic advantages over monovalent bispecific constructs. To identify a potential immunotherapeutic for AML and other CD33+ hematologic malignancies, fully human T-cell recruiting, CD33-directed bispecific TandAbs were constructed and profiled for manufacturability, stability and pharmacologic activity.Methods: Anti-CD33 scFv with high affinity to both human and cynomolgus CD33 were selected from fully human scFv libraries using phage display. Stable anti-CD33 scFv were formatted into TandAbs; linker length and domain order/topology were also varied. Expression levels in stably transfected CHO cells, purification properties, and stability were evaluated. Mechanism-based functional assays measured CD33/CD3 TandAb-mediated cytotoxicity towards CD33+ target cells. T cell activation and proliferation in the presence and absence of target cells were also studied. In vitro safety assessments of specificity and cytokine release from T cells without target cells were performed. CD33/CD3 TandAbs were studied in prophylactic and established HL-60 xenograft models. Results: CD33/CD3 TandAbs with excellent production and stability profiles also had potent cytotoxic activity towards CD33+ target cells (EC50 < 10 pM). TandAbs demonstrated equivalent binding affinity and potency for human and cyno antigens, facilitating toxicity studies. T cell activation, proliferation and cytotoxicity were strictly linked to the presence of CD33+ target cells. CD33/CD3 TandAbs did not elicit cytokine release from T cells without target cells. Potent anti-tumor activity of CD33/CD3 TandAbs was observed in vivo. Conclusions: A human CD33/CD3 TandAb therapeutic candidate with a promising activity and safety profile to date warrants clinical development as a potential treatment for AML. Preclinical development is ongoing.

J Clin Oncol 33, 2015 (suppl; abstr 7071) (též poster, slide)

Datum přednesení příspěvku: 31. 5. 2015