Lorvotuzumab mertansine, a CD56-targeting antibody-drug conjugate with potent antitumor activity against small cell lung cancer in human xenograft models

Abstract

(2014) Lorvotuzumab mertansine, a CD56-targeting antibody-drug conjugate with potent antitumor activity against small cell lung cancer in human xenograft models, mAbs, 6:2, 556-566,

CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer

“…Of note, other immune checkpoint ligands, such as CD80 (B7-1), CD86 (B7-2), PD-L1 (CD274), or PD-L2 (CD273), were not appreciably expressed on the surface of the SCLC samples (Supplemental Table 2); accordingly, very low expression of these cell-surface antigens was found in RNA analyses of cell lines and bulk tumors (Supplemental Figure 1, C and D) (36). Another highly expressed antigen across all samples was CD56 (neural cell adhesion molecule [NCAM]), a known marker of neuroendocrine tumors (34) and a therapeutic target currently under evaluation for SCLC (37,38), validating our approach. A number of other highly expressed surface antigens were also identified that could potentially be targeted by monoclonal antibody therapies, including CD24 (33), CD29, and CD99 (see below).…”

“…Specifically, we tested antibodies to CD56 (clones HCD56 and MEM-188), CD24, CD29, and CD99. Additionally, we obtained the sequence for lorvotuzumab, an anti-CD56 antibody being evaluated in clinical trials as an antibody-drug conjugate (38), and we produced it recombinantly as a naked antibody. We tested these antibodies alone and in combination with the high-affinity CD47 antagonist CV1 (10), which blocks CD47 but does not contribute an additional Fc stimulus ( Figure 6, C and D).…”

“…Since lorvotuzumab has been under evaluation as a therapeutic agent for SCLC (38), we investigated its ability to induce phagocytosis over a varying range of concentrations. Treatment with lorvotuzumab alone produced a dose-response relationship for inducing macrophage phagocytosis.…”

Emerging strategies for the treatment of advanced small cell lung cancer

“…Another ADC that has been assessed in SCLC is lorvotuzumab mertansine, involving a CD56 binding antibody conjugated to a microtubule inhibitor DM-1. While preclinical and phase I data for lorvotuzumab mertansine appeared promising, the phase II trial investigating its role in combination with carboplatin/ etoposide in the first line SCLC setting was discontinued due to a lack of efficacy and possible increased risk of infection and infection-related deaths (25).…”

Differential killing of CD56-expressing cells by drug-conjugated human antibodies targeting membrane-distal and membrane-proximal non-overlapping epitopes

“…The two domains may have different roles in its function: the IgGlike domains participated in homophilic interaction with another CD56 molecule on the opposite cell or next molecules on the same cell, 4 while the fibronectin type III-like domain may mediate signaling to down-stream proteins. CD56 is overexpressed in almost all neuroblastoma, 5 98% of small cell lung cancer 6,7 and 78% of multiple myeloma 8 patients. Some ovarian cancers, acute myeloid leukemia, and Wilms tumor 9 patients also have elevated CD56, 10 highlighting the widespread appeal of developing new therapies targeting CD56.…”