Nature Med: Combination of GD2 and CD47 antibody drug shows broad-spectrum anti-cancer potential

Written by | Zhou Yebin

Written | Written by Zhou Yebin | Written by Zhou Yebin

GD2 is overexpressed on a variety of solid tumors and is one of the most representative tumor surface antigens
.
GD2-targeted monoclonal antibody drugs have significant efficacy in high-risk neuroblastoma, greatly improving the prognosis of patients with this type of childhood

tumor .

Childhood Lung Cancer Immunization

The main anticancer mechanism of GD2 monoclonal antibody in neuroblastoma is through the antibody-mediated killing effect (ADCC) of natural killer cells (NK cells).
ADCC is also the main effect of CD20 antibody drugs such as rituximab in lymphoma.
mechanism
.
In addition to NK cells, macrophages in the tumor microenvironment also have the potential to kill cancer cells through antibody-mediated phagocytosis

.

Antibody drugs targeting CD47 have also shown promise in early clinical trials, especially when combined with rituximab in patients with rituximab-resistant lymphoma, tumor remissions were observed

Dr.

 

The researchers first tried to explore the synergistic ability of GD2 and CD47 antibody drugs in the most well-validated neuroblastoma model of GD2 antibody drugs

.

In the neuroblastoma xenograft mouse model with MYCN amplification, neither GD2 nor CD47 alone had obvious anti-tumor effect, but the combination could clear the tumor and achieve long-term survival
.
The combination also did not produce significant toxic side effects in mice

.

In the neuroblastoma xenograft mouse model with MYCN amplification, neither GD2 nor CD47 alone had obvious anti-tumor effect, but the combination could clear the tumor and achieve long-term survival

The combination of GD2 and CD47 antibody drug has stronger macrophage phagocytosis (a, b); also has better antitumor effect in neuroblastoma animal model (cf)

The combination of GD2 and CD47 antibody drug has stronger macrophage phagocytosis (a, b); also has better antitumor effect in neuroblastoma animal model (cf)

In order to explore the mechanism of the synergistic effect of GD2 and CD47 antibodies, the researchers used CSF1R antibody to clear myeloid cells in mice, and found that the anti-tumor effect of GD2 and CD47 antibodies disappeared, while clearing neutrophils did not affect the effectiveness

.

These experiments demonstrate that GD2 and CD47 antibodies can kill tumors through myeloid cells such as monocytes/macrophages

Antitumor effects of GD2 and CD47 antibodies depend on monocytes/macrophages

Antitumor effects of GD2 and CD47 antibodies depend on monocytes/macrophages

Can any tumor-targeting antibody drug work synergistically with the CD47 antibody that promotes macrophage phagocytosis of cancer cells? To answer this question, the researchers examined another tumor antigen target, B7-H3, and found that the combination of B7-H3 antibody and CD47 antibody did not enhance the antitumor effect of CD47

.

This shows that GD2 has its own special features, contributing to the synergistic effect with CD47 antibody drugs
.

Further mechanistic studies found that GD2 antibodies can promote cooperation with CD47 antibodies for two reasons
.
One is that the combination of GD2 antibody and GD2 will directly kill tumor cells and increase the expression of calreticulin (calreticulin) on the cell surface, which is an “eat me” signal for macrophages to promote phagocytosis
.
Second, the researchers found that GD2 interacts with Siglec-7, a cell-surface receptor that plays an immunosuppressive role
.
GD2 antibody can break the combination of the two, which may block the immunosuppressive effect of Siglec-7
.

GD2 antibodies may facilitate cooperation with CD47 antibodies for two reasons
.

The principle hypothesis of the synergistic effect of GD2 and CD47 antibody drugs

The principle hypothesis of the synergistic effect of GD2 and CD47 antibody drugs

After exploring the mechanism of synergy between GD2 and CD47 antibodies in a neuroblastoma model, the researchers set out to test whether the combination therapy would be effective in other GD2-expressing tumors
.
Although childhood osteosarcoma and adult small cell lung cancer also express GD2, neither GD2 antibody has shown efficacy in previous clinical trials
.
In mouse models of these two tumors, the researchers found that the GD2 antibody or CD47 antibody was not effective alone, but the combination had a very good anti-tumor effect
.

It has a very good anti-tumor effect when used in combination
.

GD2 combined with CD47 antibody showed efficacy in osteosarcoma mouse models (primary tumor model bd; lung metastasis model e, f)

GD2 combined with CD47 antibody showed efficacy in osteosarcoma mouse models (primary tumor model bd; lung metastasis model e, f)

Finally, the researchers found that the combination of GD2 and CD47 antibody increased the number of macrophages in the tumor, and at the same time, the phenotypic characteristics of these macrophages favored the M1 type that promotes immune activation and anti-tumor
.
However, the effect of combination therapy may still be limited by the amount of tumor GD2 expression, and the antitumor effect observed in the neuroblastoma model with the highest expression is better than that in osteosarcoma or small cell lung cancer models
.
Using the same neuroblastoma cell line, cells with high GD2 expression also corresponded to better antitumor results in vivo
.

Finally, the researchers found that the combination of GD2 and CD47 antibody increased the number of macrophages in the tumor, and at the same time, the phenotypic characteristics of these macrophages favored the M1 type that promotes immune activation and anti-tumor
.

Combining the full text, the researchers found that GD2 antibody can stimulate signals that promote phagocytosis, and has a good potential in combination with CD47 antibody targeting macrophage phagocytosis
.
Not only in neuroblastoma models, the effect of the combination of the two antibodies can be observed in GD2-expressing osteosarcoma and small cell lung cancer animal models
.

The researchers found that GD2 antibody can stimulate the signal that promotes phagocytosis, and has good potential in combination with CD47 antibody targeting macrophage phagocytosis
.
The researchers found that GD2 antibody can stimulate the signal that promotes phagocytosis, and has good potential in combination with CD47 antibody targeting macrophage phagocytosis
.

Neuroblastoma is more infiltrated by NK cells, the immune cells that dominate the killing of GD2 antibodies, and macrophages in this tumor are thought to play a suppressive role
.
By adding CD47 antibody, macrophages can also play a tumor-killing role, which may improve the efficacy of GD2 antibody in neuroblastoma
.
Combination therapy may also be suitable for osteosarcoma and small cell lung cancer for which GD2 alone is ineffective, further expanding the use of GD2 antibodies
.

Therefore, this study has strong translational application prospects.
In fact, based on the findings in the paper, the first neuroblastoma/osteosarcoma clinical trial combining GD2 mAb and CD47 mAb has been launched (NCT04751383)
.
In addition to expanding and optimizing the translational medical significance of GD2 antibody therapy, the mechanism exploration in the study also provides ideas for finding a "partner" for the "phagocytosis" checkpoint drug CD47 antibody
.

This research has strong translational application prospects.
In fact, based on the findings in the paper, the first neuroblastoma/osteosarcoma clinical trial combining GD2 mAb and CD47 mAb has been launched (NCT04751383)
.
This research has strong translational application prospects.
In fact, based on the findings in the paper, the first neuroblastoma/osteosarcoma clinical trial combining GD2 mAb and CD47 mAb has been launched (NCT04751383)
.

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Original source:

Theruvath J, Menard M, Smith BAH, Linde MH, Coles GL, Dalton GN, Wu W, Kiru L, Delaidelli A, Sotillo E, Silberstein JL, Geraghty AC, Banuelos A, Radosevich MT, Dhingra S, Heitzeneder S, Tousley A , Lattin J, Xu P, Huang J, Nasholm N, He A, Kuo TC, Sangalang ERB, Pons J, Barkal A, Brewer RE, Marjon KD, Vilches-Moure JG, Marshall PL, Fernandes R, Monje M, Cochran JR , Sorensen PH, Daldrup-Link HE, Weissman IL, Sage J, Majeti R, Bertozzi CR, Weiss WA, Mackall CL, Majzner RG.
Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication.
Nat Med.
2022 Jan 13.
doi : 10.
1038/s41591-021-01625-x

Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication.
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