A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells

Piccione, Emily; Juárez, Silvia; Liu, Jie; Tseng, Serena; Ryan, Christine E.; Narayanan, C. H.; Wang, Limin; Weiskopf, Kipp; Majeti, Ravindra

doi:10.1080/19420862.2015.1062192

Cited by 126 publications

(128 citation statements)

References 43 publications

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“…37 In short, A431 cells were pre-incubated (or not) with excess amounts of mAb 425 (50 µg/ml) for 15 min at 4°C, after which PD-L1xEGFR or PD-L1xMock was added in a concentration range from 0.01 to 50 µg/ml, in the presence of an APC-labeled PD-L1-blocking mAb (8 µg/ml). After 45 min the tumor cell-bound APC levels were quantified by flow cytometry.…”

Section: Methodsmentioning

confidence: 99%

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

et al. 2018

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PD-L1-blocking antibodies produce significant clinical benefit in selected cancer patients by reactivating functionally-impaired antigen-experienced anticancer T cells. However, the efficacy of current PD-L1-blocking antibodies is potentially reduced by ‘on-target/off-tumor’ binding to PD-L1 widely expressed on normal cells. This lack of tumor selectivity may induce a generalized activation of all antigen-experienced T cells which may explain the frequent occurrence of autoimmune-related adverse events during and after treatment.To address these issues, we constructed a bispecific antibody (bsAb), designated PD-L1xEGFR, to direct PD-L1-blockade to EGFR-expressing cancer cells and to more selectively reactivate anticancer T cells. Indeed, the IC50 of PD-L1xEGFR for blocking PD-L1 on EGFR+ cancer cells was ∼140 fold lower compared to that of the analogous PD-L1-blocking bsAb PD-L1xMock with irrelevant target antigen specificity. Importantly, activation status, IFN-γ production, and oncolytic activity of anti-CD3xanti-EpCAM-redirected T cells was enhanced when cocultured with EGFR-expressing carcinoma cells. Similarly, the capacity of PD-L1xEGFR to promote proliferation and IFN-γ production by CMVpp65-directed CD8+ effector T cells was enhanced when cocultured with EGFR-expressing CMVpp65-transfected cancer cells. In contrast, the clinically-used PD-L1-blocking antibody MEDI4736 (durvalumab) promoted T cell activation indiscriminate of EGFR expression on cancer cells. Additionally, in mice xenografted with EGFR-expressing cancer cells 111In-PD-L1xEGFR showed a significantly higher tumor uptake compared to 111In-PD-L1xMock. In conclusion, PD-L1xEGFR blocks the PD-1/PD-L1 immune checkpoint in an EGFR-directed manner, thereby promoting the selective reactivation of anticancer T cells. This novel targeted approach may be useful to enhance efficacy and safety of PD-1/PD-L1 checkpoint blockade in EGFR-overexpressing malignancies.

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Section: Methodsmentioning

confidence: 99%

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

et al. 2018

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“…Well-controlled affinity is one of these. 39,68 Moreover, the proper balance of target affinity and avidity is critical to ascertain high efficacy with reduced undesired side-effects. 68 As the CODV design guarantees unobstructed paratopes and stable VH/VL dimerization, it fulfils these requirements.…”

Section: Discussionmentioning

confidence: 99%

“…[30][31][32][33][34][35] Furthermore, they may elicit antibody-dependent cell-mediated cytotoxicity or phagocytosis (ADCC or ADCP, respectively) via Fcg receptors (FcgRs), which is important for cancer biotherapeutics. 3,[36][37][38][39] Fully functional Fc domains may also confer the potential to trigger the classical pathway of complementdependent humoral response, and thereby elicit complementdependent cytotoxicity (CDC). 40,41 To overcome major limitations of existing bispecific biotherapeutics and to create a universally applicable format that can be fine-tuned in multiparametric drug optimization, we designed the CODV format to serve as a versatile platform for the development of bispecific agents.…”

Section: Introductionmentioning

confidence: 99%

CODV-Ig, a universal bispecific tetravalent and multifunctional immunoglobulin format for medical applications

Steinmetz

Vallée

Beil

et al. 2016

mAbs

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Bispecific immunoglobulins (Igs) typically contain at least two distinct variable domains (Fv) that bind to two different target proteins. They are conceived to facilitate clinical development of biotherapeutic agents for diseases where improved clinical outcome is obtained or expected by combination therapy compared to treatment by single agents. Almost all existing formats are linear in their concept and differ widely in drug-like and manufacture-related properties. To overcome their major limitations, we designed cross-over dual variable Ig-like proteins (CODV-Ig). Their design is akin to the design of circularly closed repeat architectures. Indeed, initial results showed that the traditional approach of utilizing (G4S) x linkers for biotherapeutics design does not identify functional CODV-Igs. Therefore, we applied an unprecedented molecular modeling strategy for linker design that consistently results in CODV-Igs with excellent biochemical and biophysical properties. CODV architecture results in a circular self-contained structure functioning as a self-supporting truss that maintains the parental antibody affinities for both antigens without positional effects. The format is universally suitable for therapeutic applications targeting both circulating and membrane-localized proteins. Due to the full functionality of the Fc domains, serum half-life extension as well as antibody-or complement-dependent cytotoxicity may support biological efficiency of CODV-Igs. We show that judicious choice in combination of epitopes and paratope orientations of bispecific biotherapeutics is anticipated to be critical for clinical outcome. Uniting the major advantages of alternative bispecific biotherapeutics, CODV-Igs are applicable in a wide range of disease areas for fast-track multi-parametric drug optimization.

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“…Nevertheless, the question remains whether this really circumvents the problem, as IgG4 antibodies may still bind efficiently to the high‐affinity human FcγRI receptor and the Hu5F9‐G4 CD47 blocking antibody may therefore still cause potential undesired effects. Furthermore, a bispecific antibody against CD47 and CD20 was recently reported . This bispecific antibody was engineered to have a relatively low affinity towards CD47, causing an overall decrease in binding to cells expressing CD47, but at the same time retaining its CD20 binding capacity .…”

Section: Cd47‐sirpα Interactions As An Immune Checkpoint In Cancermentioning

confidence: 99%

The CD47‐SIRPα signaling axis as an innate immune checkpoint in cancer

Matlung

Szilagyi

Barclay

et al. 2017

Immunological Reviews

440

353

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Immune checkpoint inhibitors, including those targeting CTLA-4/B7 and the PD-1/PD-L1 inhibitory pathways, are now available for clinical use in cancer patients, with other interesting checkpoint inhibitors being currently in development. Most of these have the purpose to promote adaptive T cell-mediated immunity against cancer. Here, we review another checkpoint acting to potentiate the activity of innate immune cells towards cancer. This innate immune checkpoint is composed of what has become known as the 'don't-eat me' signal CD47, which is a protein broadly expressed on normal cells and often overexpressed on cancer cells, and its counter-receptor, the myeloid inhibitory immunoreceptor SIRPα. Blocking CD47-SIRPα interactions has been shown to promote the destruction of cancer cells by phagocytes, including macrophages and neutrophils. Furthermore, there is growing evidence that targeting of the CD47-SIRPα axis may also promote antigen-presenting cell function and thereby stimulate adaptive T cell-mediated anti-cancer immunity. The development of CD47-SIRPα checkpoint inhibitors and the potential side effects that these may have are discussed. Collectively, this identifies the CD47-SIRPα axis as a promising innate immune checkpoint in cancer, and with data of the first clinical studies with CD47-SIRPα checkpoint inhibitors expected within the coming years, this is an exciting and rapidly developing field.

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A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells

Cited by 126 publications

References 43 publications

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

CODV-Ig, a universal bispecific tetravalent and multifunctional immunoglobulin format for medical applications

The CD47‐SIRPα signaling axis as an innate immune checkpoint in cancer

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