CD20-selective inhibition of CD47-SIRP alpha "don't eat me" signaling with a bispecific antibody-derivative enhances the anticancer activity of daratumumab, alemtuzumab and obinutuzumab

Peter E. van Bommel; Yuan He; Ilona Schepel; Mark A. J. M. Hendriks; Valerie R. Wiersma; Robert J. van Ginkel; Tom van Meerten; Emanuele Ammatuna; Gerwin Huls; Douwe F. Samplonius; Wijnand Helfrich; Edwin Bremer

doi:10.1080/2162402X.2017.1386361

CD20-selective inhibition of CD47-SIRP alpha "don't eat me" signaling with a bispecific antibody-derivative enhances the anticancer activity of daratumumab, alemtuzumab and obinutuzumab

Peter E. van Bommel, Yuan He, Ilona Schepel, Mark A. J. M. Hendriks, Valerie R. Wiersma, Robert J. van Ginkel, Tom van Meerten, Emanuele Ammatuna, Gerwin Huls, Douwe F. Samplonius, Wijnand Helfrich^*, Edwin Bremer

^*Bijbehorende auteur voor dit werk

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Here, we report on a novel bispecific antibody-derivative, designated RTX-CD47, with unique capacity for CD20-directed inhibition of CD47-SIRP alpha "don't eat me" signaling. RTX-CD47 comprises a CD20-targeting scFv antibody fragment derived from rituximab fused in tandem to a CD47-blocking scFv. Single agent treatment with RTX-CD47 triggered significant phagocytic removal of CD20(pos)/CD47(pos) malignant B-cells, but not of CD20(neg)/CD47(pos) cells, and required no pro-phagocytic FcR-mediated signaling. Importantly, treatment with RTX-CD47 synergistically enhanced the phagocytic elimination of primary malignant B cells by autologous phagocytic effector cells as induced by therapeutic anticancer antibodies daratumumab (anti-CD38), alemtuzumab (anti-CD52) and obinutuzumab (anti-CD20). In conclusion, RTX-CD47 blocks CD47 "don't eat me" signaling by cancer cells in a CD20-directed manner with essentially no activity towards CD20(neg)/CD47(pos) cells and enhances the activity of therapeutic anticancer antibodies directed to B-cell malignancies.

Originele taal-2	English
Artikelnummer	e1386361
Aantal pagina's	8
Tijdschrift	OncoImmunology
Volume	7
Nummer van het tijdschrift	2
DOI's	https://doi.org/10.1080/2162402X.2017.1386361
Status	Published - 2018

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10.1080/2162402X.2017.1386361Licentie: CC BY-NC-ND

CD20-selective inhibition of CD47-SIRPα “don't eat me” signaling with a bispecific antibody-derivative enhances the anticancer activity of daratumumab, alemtuzumab and obinutuzumabFinal publisher's version, 1,41 MBLicentie: CC BY-NC-ND

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van Bommel, P. E., He, Y., Schepel, I., Hendriks, M. A. J. M., Wiersma, V. R., van Ginkel, R. J., van Meerten, T., Ammatuna, E., Huls, G., Samplonius, D. F., Helfrich, W., & Bremer, E. (2018). CD20-selective inhibition of CD47-SIRP alpha "don't eat me" signaling with a bispecific antibody-derivative enhances the anticancer activity of daratumumab, alemtuzumab and obinutuzumab. OncoImmunology, 7(2), [e1386361]. https://doi.org/10.1080/2162402X.2017.1386361

@article{07e98ff419994554a63c5e03f40f678e,

title = "CD20-selective inhibition of CD47-SIRP alpha {"}don't eat me{"} signaling with a bispecific antibody-derivative enhances the anticancer activity of daratumumab, alemtuzumab and obinutuzumab",

abstract = "Here, we report on a novel bispecific antibody-derivative, designated RTX-CD47, with unique capacity for CD20-directed inhibition of CD47-SIRP alpha {"}don't eat me{"} signaling. RTX-CD47 comprises a CD20-targeting scFv antibody fragment derived from rituximab fused in tandem to a CD47-blocking scFv. Single agent treatment with RTX-CD47 triggered significant phagocytic removal of CD20(pos)/CD47(pos) malignant B-cells, but not of CD20(neg)/CD47(pos) cells, and required no pro-phagocytic FcR-mediated signaling. Importantly, treatment with RTX-CD47 synergistically enhanced the phagocytic elimination of primary malignant B cells by autologous phagocytic effector cells as induced by therapeutic anticancer antibodies daratumumab (anti-CD38), alemtuzumab (anti-CD52) and obinutuzumab (anti-CD20). In conclusion, RTX-CD47 blocks CD47 {"}don't eat me{"} signaling by cancer cells in a CD20-directed manner with essentially no activity towards CD20(neg)/CD47(pos) cells and enhances the activity of therapeutic anticancer antibodies directed to B-cell malignancies.",

keywords = "bispecific antibody, CD47, phagocytosis, rituximab, SIRP, STEM-CELLS, PHAGOCYTOSIS, TARGET, SELECTIVITY, LYMPHOMA, BLOCKADE, PROTEIN, TUMORS, ALPHA",

author = "{van Bommel}, {Peter E.} and Yuan He and Ilona Schepel and Hendriks, {Mark A. J. M.} and Wiersma, {Valerie R.} and {van Ginkel}, {Robert J.} and {van Meerten}, Tom and Emanuele Ammatuna and Gerwin Huls and Samplonius, {Douwe F.} and Wijnand Helfrich and Edwin Bremer",

year = "2018",

doi = "10.1080/2162402X.2017.1386361",

language = "English",

volume = "7",

journal = "OncoImmunology",

issn = "2162-4011",

publisher = "Taylor & Francis Group",

number = "2",

}

van Bommel, PE, He, Y, Schepel, I, Hendriks, MAJM , Wiersma, VR , van Ginkel, RJ , van Meerten, T , Ammatuna, E , Huls, G , Samplonius, DF , Helfrich, W & Bremer, E 2018, 'CD20-selective inhibition of CD47-SIRP alpha "don't eat me" signaling with a bispecific antibody-derivative enhances the anticancer activity of daratumumab, alemtuzumab and obinutuzumab', OncoImmunology, vol. 7, nr. 2, e1386361. https://doi.org/10.1080/2162402X.2017.1386361

TY - JOUR

T1 - CD20-selective inhibition of CD47-SIRP alpha "don't eat me" signaling with a bispecific antibody-derivative enhances the anticancer activity of daratumumab, alemtuzumab and obinutuzumab

AU - van Bommel, Peter E.

AU - He, Yuan

AU - Schepel, Ilona

AU - Hendriks, Mark A. J. M.

AU - Wiersma, Valerie R.

AU - van Ginkel, Robert J.

AU - van Meerten, Tom

AU - Ammatuna, Emanuele

AU - Huls, Gerwin

AU - Samplonius, Douwe F.

AU - Helfrich, Wijnand

AU - Bremer, Edwin

PY - 2018

Y1 - 2018

N2 - Here, we report on a novel bispecific antibody-derivative, designated RTX-CD47, with unique capacity for CD20-directed inhibition of CD47-SIRP alpha "don't eat me" signaling. RTX-CD47 comprises a CD20-targeting scFv antibody fragment derived from rituximab fused in tandem to a CD47-blocking scFv. Single agent treatment with RTX-CD47 triggered significant phagocytic removal of CD20(pos)/CD47(pos) malignant B-cells, but not of CD20(neg)/CD47(pos) cells, and required no pro-phagocytic FcR-mediated signaling. Importantly, treatment with RTX-CD47 synergistically enhanced the phagocytic elimination of primary malignant B cells by autologous phagocytic effector cells as induced by therapeutic anticancer antibodies daratumumab (anti-CD38), alemtuzumab (anti-CD52) and obinutuzumab (anti-CD20). In conclusion, RTX-CD47 blocks CD47 "don't eat me" signaling by cancer cells in a CD20-directed manner with essentially no activity towards CD20(neg)/CD47(pos) cells and enhances the activity of therapeutic anticancer antibodies directed to B-cell malignancies.

AB - Here, we report on a novel bispecific antibody-derivative, designated RTX-CD47, with unique capacity for CD20-directed inhibition of CD47-SIRP alpha "don't eat me" signaling. RTX-CD47 comprises a CD20-targeting scFv antibody fragment derived from rituximab fused in tandem to a CD47-blocking scFv. Single agent treatment with RTX-CD47 triggered significant phagocytic removal of CD20(pos)/CD47(pos) malignant B-cells, but not of CD20(neg)/CD47(pos) cells, and required no pro-phagocytic FcR-mediated signaling. Importantly, treatment with RTX-CD47 synergistically enhanced the phagocytic elimination of primary malignant B cells by autologous phagocytic effector cells as induced by therapeutic anticancer antibodies daratumumab (anti-CD38), alemtuzumab (anti-CD52) and obinutuzumab (anti-CD20). In conclusion, RTX-CD47 blocks CD47 "don't eat me" signaling by cancer cells in a CD20-directed manner with essentially no activity towards CD20(neg)/CD47(pos) cells and enhances the activity of therapeutic anticancer antibodies directed to B-cell malignancies.

KW - bispecific antibody

KW - CD47

KW - phagocytosis

KW - rituximab

KW - SIRP

KW - STEM-CELLS

KW - PHAGOCYTOSIS

KW - TARGET

KW - SELECTIVITY

KW - LYMPHOMA

KW - BLOCKADE

KW - PROTEIN

KW - TUMORS

KW - ALPHA

U2 - 10.1080/2162402X.2017.1386361

DO - 10.1080/2162402X.2017.1386361

M3 - Article

C2 - 29308308

AN - SCOPUS:85032696888

SN - 2162-4011

VL - 7

JO - OncoImmunology

JF - OncoImmunology

IS - 2

M1 - e1386361

ER -