Overcoming leukemia heterogeneity by combining T cell engaging bispecific antibodies

Abstract

BackgroundLeukemia represents about 5% of all human cancers. Despite advances in therapeutics, a substantial number of patients succumb to the disease. Several subtypes of leukemia are inherently more resistant to treatment despite intensive chemotherapy or targeted therapy.MethodsHere we describe the generation of T cell engaging (CD3) bispecific antibodies (BsAbs) built on humanized IgG frameworks using the IgG(L)-scFv format against two targets expressed on acute lymphoblastic leukemia (ALL) and on acute myeloid leukemia (AML).ResultsEach BsAb mediated potent anti-leukemia effect against ALL (CD19) and AML (CD33) in vitro and in xenograft models. Importantly, the CD19-specific BsAb (BC250) was effective against hematogenous spread preventing metastases to liver and kidney in mice bearing ALL and Burkitt’s lymphoma xenografts. BC250 was more potent than the The Food and Drug Administration (FDA)-approved BsAb blinatumomab against ALL xenografts in vivo as measured by tumor bioluminescence and mouse survival. Furthermore, the combination of the CD19 and CD33 BsAbs in two xenograft models of mixed phenotype acute leukemia (biphenotypic and bilineal leukemia) was far superior than monotherapy with either of the BsAbs alone.ConclusionsSelective combinations of these leukemia-specific BsAb offer the potential to overcome tumor heterogeneity or clonal escape in the modern era of antibody-based T cell-driven immunotherapy.

Bispecific Antibodies in Hematological Malignancies: A Scoping Review

“…Another potential mechanism of resistance is the possibility of a myeloid lineage switch following blinatumomab therapy, particularly in KMT2A(MLL)-rearranged ALL, which may lead to the development of AML [ 89 , 90 , 91 , 92 ]. A recent preclinical study evaluated the possibility of combining anti-CD19 and anti-CD33 BiAbs to target tumor heterogeneity and prevent clonal escape [ 93 ].…”

“…Another potential mechanism of resistance is the possibility of a myeloid lineage switch following blinatumomab therapy, particularly in KMT2A(MLL)-rearranged ALL, which may lead to the development of AML [89][90][91][92]. A recent preclinical study evaluated the possibility of combining anti-CD19 and anti-CD33 BiAbs to target tumor heterogeneity and prevent clonal escape [93]. (2) myeloid lineage switch after blinatumomab therapy, which has been reported in cases of KMT2A(MLL)-rearranged acute lymphoblastic leukemia, resulting in the development of acute myelogenous leukemia; (3) the immunosuppressive microenvironment in acute lymphoblastic leukemia is associated with an increased percentage of regulatory T cells along with a lower frequency of CD8+/CD3+ T cells, thereby facilitating resistance to blinatumomab.…”

Immunotherapy approaches for hematological cancers

“…In diffuse large B-cell lymphoma patients, 56% demonstrated a response to blinatumomab ( Topp et al., 2011 ; Suresh et al., 2014 ). Other studies are being done to find other promising bispecific antibodies for leukemia and lymphoma, and the CD19-specific bispecific antibody (BC250) was found more effective than blinatumomab against ALL xenografts in vivo ( Hoseini et al., 2020 ).…”

Pediatric Mixed-Phenotype Acute Leukemia: What’s New?

“…Given the presence of different lineage antigens in MPAL, it is thought that bi-specific immunotherapy options might be more efficacious. Pre-clinical data have shown that dual-targeting triplebody therapy directed against CD33/CD3/CD19 leads to selective and effective lysis of biphenotypic B/myeloid cells expressing CD19 and CD33 [ 82 , 83 ]. A recent case report successfully utilized two immunotherapy options targeting separate antigens (Blinatumomab for CD19 and Gemtuzumab for CD33) to successfully treat a refractory, KMT2A-rearranged infant MPAL [ 37 ].…”