Table 1 Summary of myeloid cell engagers described in cancer and HIV

Macrophages and neutrophils (FcγRI)

Anti-CD30 × anti-FcγRI (H22xKi4)

Lymphoma

In vitro:

Yes, Phase I (discontinued)

[109, 110]

• H22xKi4 binds to CD30⁺ cells

• H22xKi4 potently mediates ADCC with CD30⁺ tumor cells and human monocytes

• H22xKi4 enhances monocyte-derived macrophages-mediated phagocytosis

Anti-HER2/neu × anti-FcγRI (H22x520C9/MDX-210)

HER2⁺ breast, ovarian or prostate cancers

In vitro:

Yes, Phase II (discontinued)

[111,112,113]

• H22x520C9/MDX-210 mediates ADCP and ADCC in the presence of monocyte-derived macrophages (MDM) against HER2⁺ target cells at similar levels than monoclonal antibody against anti-HER2/neu

Humanized anti-HER2 × anti-FcγRI (MDX-H210)

HER2⁺ breast, ovarian or prostate cancers

In vitro:

Yes, Phase II (discontinued)

[111, 112, 114]

• MDX-H210 mediates ADCP to a similar level than MDX-210

Anti-EGFR × anti-FcγRI (MDX-447)

EGFR⁺ tumors

In vitro:

Yes, Phase II (discontinued)

[115, 116]

• MDX-447 binds to EGFR⁺ and FcγRI⁺ cells

• MDX-447 mediates ADCC and lysis of EGFR-overexpressing cell lines

Anti-EpCAM × anti-FcγRI (HEA125x197)

Ovarian carcinoma and other EpCAM⁺ carcinomas

In vitro:

No

[117]

• HEA125x197 binds to EpCAM⁺ and FcγRI⁺ cells

• HEA125x197 induces potent cytotoxic activity towards allogeneic and autologous ovarian carcinoma cells in the presence of stimulated CD64⁺ polymorphonuclear neutrophils (PMN)

Anti-gp41 × anti-FcγRI (MDX-240)

HIV

In vitro:

Yes, Phase II (discontinued)

[87]

• MDX-240 mediates viral inhibition infection of PBMCs and human macrophages

• MDX-240 reverses ongoing in vitro HIV-1 human macrophage infection

Macrophages and neutrophils (SIRPα)

Anti-SIRPα × anti-CD70

Non-Hodgkin lymphoma, multiple myeloma, renal cell carcinoma, and glioblastoma

In vitro:

No

[78]

• The construct enhances macrophage phagocytosis of renal carcinoma cells, an effect not observed with the combination of monoclonal antibodies anti-SIRPα and anti-CD70

In vivo:

• The construct inhibits Burkitt’s lymphoma cell growth in SRG mice, but not better than the combination of monoclonal antibodies

Macrophages and neutrophils (FcαRI)

Anti-CD30 × anti-FcαRI (A77xKi4)

Lymphoma

In vitro:

No

[109]

• A77xKi4 binds to CD30⁺ cells

• A77xKi4 potently mediates ADCC of CD30⁺ tumor cells by human monocytes

• A77xKi4 partially mediates ADCC of freshly prepared PMN leukocytes against CD30⁺ cells

• A77xKi4 enhances monocyte-derived macrophages-mediated phagocytosis

Anti-HER-2/neu × anti-FcαRI (A77x520C9)

HER2⁺ carcinomas

In vitro:

No

[118, 119]

• A77x520C9 induces phagocytosis of breast cancer cell lines by human macrophages, at similar rate than H22x520C9 (anti-HER2/neu × anti-FcγRI)

• Macrophages treated with GM-CSF, but not INF-γ, induce more efficient phagocytosis of breast cancer cells by macrophages in presence of A77x520C9

• A77x520C9 induces breast cancer cell lines autophagy (and not apoptosis) when incubated with human PMN

Anti-CD20 × anti-FcαRI

B cell malignancies and lung cancer

In vitro

No

[76]

• The construct binds to CD20⁺ cells (Raji cells) and FcαRI⁺ cells (PMN)

• The construct mediates ADCC of Raji cells via human PMN

In vivo

• The construct enhances the regression of Raji cells tumors in NOD/SCID mice in the presence of PMN

• Tumor cell killing of Lewis lung cancer (LLC) cells transfected with human CD20 (LLC-hCD20) in FcαRI Tg mice is enhanced in the presence of the bispecific construct

• Tumor associated macrophages (TAM) isolated from LLC-hCD20 mice mediate ADCP of Raji cells in the presence of the bispecific construct

Anti-HER-2 × IgGA

HER2⁺ carcinomas

In vitro

No

[82]

• The construct binds to FcαRI, FcγRI and FcγRIIa due to engineered “cross-isotype” antibody IgGA

• The construct mediates HER2⁺ cancer cells killing by ADCC and ADCP, by both macrophages and neutrophils

• Complement-dependent cytotoxicity (CDC) is improved in the presence of the cross-isotype construct compared to IgG1 or IgA antibodies

Anti-HER-2 × IgG1/IgA2

HER2⁺ carcinomas

In vitro

No

[83]

• The construct stimulates ADCC activity of NK cells and freshly isolated PMN cells against HER2⁺ cells

• ADCP activity by macrophages against SK-BR3 and MDA-MB-453 cells is enhanced in the presence of the construct

• The construct increases the recruitment and cytotoxic functions of PMN against HER2⁺ cell lines in comparison to IgG1 or IgA2

In vivo

• The construct shows improved pharmacokinetic properties in BALB/c mice compared to parental IgA2 (better serum persistence)

Anti-CD20 × IgGA

B cell malignancies

Ex vivo

No

[84]

• Tumor cell killing of Raji cells by both human myeloid effector cells and Tg is enhanced in thepresence of the IgGA construct compared to CD20-IgG or CD20-IgA

In vivo

• FcαRI Tg mice treated with the IgGA construct show enhanced tumor cell killing of Lewis lung cancer (LLC) cells transfected with human CD20 (LLC-hCD20), compared to CD20-IgG or CD20-IgA

Anti-EGFR × anti-FcαRI × anti-FcγRI (TrisomAb)

Colorectal cancer

In vitro

No

[85]

• anti-EGFR TrisomAb induces FcγRI mediated ADCC (by NK cells) and ADCP (by macrophages) of EGFR⁺ cells

• anti-EGFR TrisomAb induces FcαRI mediated cytotoxicity of EGFR⁺ cells by neutrophils

• Colorectal cancer patients-derived neutrophils effectively eliminates tumor cells in the presence of anti-EGFR TrisomAb

Anti-gp75 × anti-FcαRI × anti-FcγRI (TrisomAb)

Melanoma

In vitro

• anti-gp75 TrisomAb induces FcγRI mediated ADCC (by NK cells) and ADCP (by macrophages) of gp75⁺ cells

• anti-gp75 TrisomAb induces FcαRI mediated cytotoxicity of gp75⁺ cells by neutrophils

In vivo

• Tumor outgrowth in FcαRI transgenic C57BL/6 mice injected subcutaneously with gp75⁺ cells is reduced in the presence of TrisomAb, by macrophages, NK cells and neutrophils

Anti-gp41 × anti-FcαRI

HIV

In vitro

No

[91]

• The bispecific-antibody-mediated destruction of HIV and HIV-infected cells by ADCVI (antibody-dependent cell-mediated virus inhibition) is induced in the presence of neutrophils

Dendritic cells

Anti-CD40 × anti-EpCAM (Neo-X-Prime/ATOR-4066)

EpCAM⁺ cancer

In vitro

No

[97]

• Binding on antigen-presenting cells (APC) and EpCAM⁺ cancer cells resulting in activation of APC

• Stimulation of delivery of necrotic tumor debris to APCs, which was not observed with monoclonal antibody against EpCAM

In vivo

• hCD40tg mice bearing MB49-EpCAM tumors and treated with anti-CD40 × anti-EpCAM show EpCAM-dependant anti-tumor effects as compared to CD40 mAb or isotype × EpCAM

• Administration of anti-CD40 × anti-EpCAM stimulates immunological memory in tumor bearing mice and prevents the growth of new MB49-EpCAM tumors

• No systemic inflammation is associated with the administration of anti-CD40 × anti-EpCAM in mice and non-human primates

Anti-CD40 × anti-CEA (Neo-X-Prime/ATOR-4066)

CEA⁺ cancer

In vitro

• Anti-CEA ATOR-4066 binds to antigen-presenting cells (APCs) and CEA⁺ cancer cells resulting in activation of APC

• Anti-CEA ATOR-4066 stimulates the delivery of necrotic tumor debris to APCs, which was not observed with monoclonal antibody against CEA

In vivo

• hCD40tg mice injected with CEA-transfected MC38 cells and administered with anti-CEA ATOR-4066 showed significant anti-tumor effects

Anti-CD40 × anti-CEA

CEA⁺ cancer

In vitro/Ex vivo

No

[96]

• Anti-CD40 × anti-CEA binds specifically to their targets and induces CEA-dependent CD40 agonism of splenic DC isolated from huCD40tg mice, resulting in enhanced T cell cross-priming

• Anti-CD40 × anti-CEA promotes the delivery of CEA⁺ beads and CEA⁺ tumor-derived extracellular vehicles (EVs) to DC, facilitating the presentation of tumor antigen and ultimately the tumor-specific T cell priming

Anti-CD40 × anti-MSLN (ABBV-428)

MSLN⁺ cancer

In vitro

Yes, Phase I (NCT02955251)

[100, 120]

• ABBV-428 induces CD40-dependent APCs activation and proliferation, only when co-cultured with MSLN⁺ cells

• ABBV-428 induces MSLN-dependent T cell activation

• The efficacy of ABBV-428 is dependent on the amount of MSLN expression, that should be above a specific threshold

In vivo

• NSG mice inoculated with MSLN⁺ tumor cells and treated with ABBV-428 show tumor regression in a specific manner

Anti-LAG3 × PDL-1 (ABL501)

Progressive, locally advanced (unresectable) or metastatic solid tumors

In vitro

Yes, Phase I (NCT05101109)

[99]

• ABL501 simultaneously blocks LAG-3 and PD-L1 and efficiently activates CD4⁺ and CD8⁺ T cells

• ABL501 compensates T_reg-cell suppressive functions towards effector T cell, with better efficacy than the monoclonal antibodies

• CD8⁺ T cell activation by ABL501 is explained by enhanced DC maturation and increased conjugation between T cells and tumor cells

In vivo

• Humanized NSG mice injected with A375-PD-L1 tumors, adoptively transferred with 1G4 TCR-T cells and administered with ABL501 showed significant tumor regression as compared to anti-PD-L1 treatment, as well as increased tumor-infiltrating lymphocytes (TILs) rate and activation

• ABL501 presents a good safety profile in mice and in cynomolgus monkeys

Anti-CD40 × anti-FAP (MP0317)

Advanced solid tumors

In vitro

Yes, Phase I (NCT05098405)

[101]

• MP0317 specifically activates APC in presence of FAP⁺ cells

In vivo

• Mice with FAP⁺ tumors (MC38 colorectal cancer cells) and administered with a murine version of MP0317 show an accumulation of the construct in the tumors

• A significant anti-tumor effect as well as an increased memory antitumor immunity was observed in the MC38-FAP mice administered with the murine version of MP0317

• No toxicity (measured by blood cytokines IL6, TNF-α, IFN-γ and IL12p70 and by the hepatotoxicity markers AST and ALT) was observed in these mice administered with the construct, as compared to the CD40-mAb