. 2022 Jun 2;52(12):1909–1924. doi: 10.1002/eji.202149515

Table 2.

Overview of CLRs used for targeting of antigen to DCs

Receptor	Expression pattern & possible ligands	Immunologic outcome after targeting
DEC‐205/CD205 (29‐35, 37–39, 47, 65–78, 82, 84, 85, 90, 94, 95, 97, 115, 118, 134–136, 138–143)	Expression by cDC1, cDC2, LCs, pDCs, and sparsely by B cells in humans;Closely related to MR Ligands: Apoptotic/necrotic cells, binding via keratins, CpG‐oligonucleotides	‐ CD4⁺ and CD8⁺ T‐cell responses as well as humoral responses are induced but immunity requires concomitant activation of DCs by adjuvants ‐ Mediates effective cross‐presentation after coupling of tumor and pathogen‐derived antigens → immunity against tumors and infections ‐ Antigen presentation by steady‐state DCs in situ leads to tolerance induction by anergy and/or regulatory T cell activation → control of autoimmunity ‐ Single chain fragment variables are available for targeting of fusion proteins ‐ Clinical trials with DEC‐205‐antibody conjugated antigens were performed and demonstrated humoral and cellular immunity against HIV and melanoma
MR/CD206 (29, 38, 55, 56, 100, 101, 144–147)	Expression by macrophage populations, moDCs and blood CD1c⁺ DCs, but also expressed by non‐antigen presenting cells such as endothelial cells. Ligands: Generally glycoproteins belonging to mannosylated /N‐acetyl‐glucosamine–terminal and fucosylated neoglycoproteins.	‐ MR ligands were firstly used for targeting approaches ‐ Mainly used as target for antigen:ligand conjugates, data on antibody‐mediated targeting are sparse ‐ Preferentially guides antigens to the cross‐presentation pathways and induces CD8⁺ T‐cell activation → tumor immunity ‐ Ligand‐coated nanoparticles, such as liposomes and dendrimers loaded with specific cargo, have successfully been used to induce tumor‐specific T cells ‐ Clinical trials have been performed with oxidized mannan ligands and antibody‐conjugated tumor antigens → humoral and cellular responses were induced against adenocarcinoma and breast cancer
DC‐SIGN/CD209 (53, 58, 59, 124–126, 128, 148–154)	Expression by moDCs and dermal CD14⁺ cells Ligands: Recognizes Lewis‐type antigens and high mannose carbohydrates	‐ Ligand‐coated antigens (i.e. mannose or Lewis‐type glycans) and glycoliposomes decorated with Lewis‐type glycans target antigens via DC‐SIGN into human DCs ‐ antibody:antigen conjugates are taken up by human moDCs and generate T‐cell immunity ‐ DC‐SIGN targeting mediates CD4⁺ and CD8⁺ T‐cell responses ‐ human‐DC‐SIGN transgenic mice, humanized mouse models, and non‐human primates were used to prove translational potential for DC‐SIGN‐targeting as tumor therapy
Dectin‐1/CD369 (111, 112, 135, 155–160)	Expression by mouse cDC2s and human monocytes, macrophages and DCs Ligands: Primary pattern recognition receptor for glucans	‐ Modifications of antigens by natural Dectin‐1 ligands induce immune responses ‐ Dectin‐1 ligand has also been used as an adjuvant due to its ITAM engaging function → promising tool to enhance efficacy of other (targeted) therapies ‐ strong CD4⁺ T cell and B‐cell responses, stimulation of specific Th17 cells ‐ CD8⁺ T‐cell responses are weaker as compared to DEC‐205 targeting
Langerin/CD207 (58, 67–69, 72, 95, 113–115, 118–121, 161, 162)	Expression by mouse and human LCs, but also by mouse dermal cDC1 and splenic cDC1 (only in BALB/c mice) Ligands: mannose, N‐Acetylglucosamine (GlcNAc) and fucose	‐ Antibody‐mediated targeting of Langerin stimulated functional CD4⁺ and CD8⁺ T‐cell responses but also humoral responses ‐ Different T‐cell responses induced by dermal cDC1 and LCs in mice → LCs tolerogenic role, whereas dermal cDC1 primed T cells ‐ Skin vaccination studies prove potential to load LCs in situ ‐ ligands coating liposomes (i.e. Lewis Y or novel glycomimetic ligand) allow delivery of antigens to human LCs → resulting in cross‐presentation to CD8⁺ T cells
DCIR2/CD367 (36, 65, 73, 135, 163)	Expression by mouse cDC2 and human pDCs Ligands: binds to N‐glycan with bisecting GlcNAc and a GlcNAc‐terminated α1‐3 branch.	‐ Targeted antigens preferentially stimulate CD4⁺ T cells but also T cell‐dependent B‐cell responses, low activation of CD8⁺ T cells ‐ in humanized mice vaccination with DCIR‐specific antibodies stimulated T cells ‐ DCIR contains an ITIM motif and may have suppressive effects on antigen targeting, thus, maybe useful for tolerance induction
CLEC9a/DNGR1/CD370 (69, 76, 103, 105–110, 164–168)	Expression by mouse and human cDC1 Ligand: binds to actin on dying cells	‐ Targeting to CLEC9a by antibody:antigen conjugates induces strong antitumor immunity via the activation of CD8⁺ T cells, partially also CD4⁺ T‐cell responses ‐ Induction of strong humoral responses, which could be induced without adjuvant in mice and non‐human primates. However, it seems crucial to determine which antibody is used for targeting as not all induce a full‐blown immune response.

Receptor

Expression pattern

& possible ligands

Immunologic outcome after targeting

DEC‐205/CD205

(29‐35, 37–39, 47, 65–78, 82, 84, 85, 90, 94, 95, 97, 115, 118, 134–136, 138–143)

Expression by cDC1, cDC2, LCs, pDCs, and sparsely by B cells in humans;Closely related to MR

Ligands: Apoptotic/necrotic cells, binding via keratins,

CpG‐oligonucleotides

‐ CD4⁺ and CD8⁺ T‐cell responses as well as humoral responses are induced but immunity requires concomitant activation of DCs by adjuvants

‐ Mediates effective cross‐presentation after coupling of tumor and pathogen‐derived antigens → immunity against tumors and infections

‐ Antigen presentation by steady‐state DCs in situ leads to tolerance induction by anergy and/or regulatory T cell activation → control of autoimmunity

‐ Single chain fragment variables are available for targeting of fusion proteins

‐ Clinical trials with DEC‐205‐antibody conjugated antigens were performed and demonstrated humoral and cellular immunity against HIV and melanoma

MR/CD206

(29, 38, 55, 56, 100, 101, 144–147)

Expression by macrophage populations, moDCs and blood CD1c⁺ DCs, but also expressed by non‐antigen presenting cells such as endothelial cells.

Ligands:

Generally glycoproteins belonging to mannosylated /N‐acetyl‐glucosamine–terminal and fucosylated neoglycoproteins.

‐ MR ligands were firstly used for targeting approaches

‐ Mainly used as target for antigen:ligand conjugates, data on antibody‐mediated targeting are sparse

‐ Preferentially guides antigens to the cross‐presentation pathways and induces CD8⁺ T‐cell activation → tumor immunity

‐ Ligand‐coated nanoparticles, such as liposomes and dendrimers loaded with specific cargo, have successfully been used to induce tumor‐specific T cells

‐ Clinical trials have been performed with oxidized mannan ligands and antibody‐conjugated tumor antigens → humoral and cellular responses were induced against adenocarcinoma and breast cancer

DC‐SIGN/CD209

(53, 58, 59, 124–126, 128, 148–154)

Expression by moDCs and dermal CD14⁺ cells

Ligands:

Recognizes Lewis‐type antigens and high mannose carbohydrates

‐ Ligand‐coated antigens (i.e. mannose or Lewis‐type glycans) and glycoliposomes decorated with Lewis‐type glycans target antigens via DC‐SIGN into human DCs

‐ antibody:antigen conjugates are taken up by human moDCs and generate T‐cell immunity

‐ DC‐SIGN targeting mediates CD4⁺ and CD8⁺ T‐cell responses

‐ human‐DC‐SIGN transgenic mice, humanized mouse models, and non‐human primates were used to prove translational potential for DC‐SIGN‐targeting as tumor therapy

Dectin‐1/CD369

(111, 112, 135, 155–160)

Expression by mouse cDC2s and human monocytes, macrophages and DCs

Ligands: Primary pattern recognition receptor for glucans

‐ Modifications of antigens by natural Dectin‐1 ligands induce immune responses

‐ Dectin‐1 ligand has also been used as an adjuvant due to its ITAM engaging function → promising tool to enhance efficacy of other (targeted) therapies

‐ strong CD4⁺ T cell and B‐cell responses, stimulation of specific Th17 cells

‐ CD8⁺ T‐cell responses are weaker as compared to DEC‐205 targeting

Langerin/CD207

(58, 67–69, 72, 95, 113–115, 118–121, 161, 162)

Expression by mouse and human LCs, but also by mouse dermal cDC1 and splenic cDC1 (only in BALB/c mice)

Ligands: mannose, N‐Acetylglucosamine (GlcNAc) and fucose

‐ Antibody‐mediated targeting of Langerin stimulated functional CD4⁺ and CD8⁺ T‐cell responses but also humoral responses

‐ Different T‐cell responses induced by dermal cDC1 and LCs in mice → LCs tolerogenic role, whereas dermal cDC1 primed T cells

‐ Skin vaccination studies prove potential to load LCs in situ

‐ ligands coating liposomes (i.e. Lewis Y or novel glycomimetic ligand) allow delivery of antigens to human LCs → resulting in cross‐presentation to CD8⁺ T cells

DCIR2/CD367

(36, 65, 73, 135, 163)

Expression by mouse cDC2 and human pDCs

Ligands: binds to N‐glycan with bisecting GlcNAc and a GlcNAc‐terminated α1‐3 branch.

‐ Targeted antigens preferentially stimulate CD4⁺ T cells but also T cell‐dependent B‐cell responses, low activation of CD8⁺ T cells

‐ in humanized mice vaccination with DCIR‐specific antibodies stimulated T cells

‐ DCIR contains an ITIM motif and may have suppressive effects on antigen targeting, thus, maybe useful for tolerance induction

CLEC9a/DNGR1/CD370

(69, 76, 103, 105–110, 164–168)

Expression by mouse and human cDC1

Ligand: binds to actin on dying cells

‐ Targeting to CLEC9a by antibody:antigen conjugates induces strong antitumor immunity via the activation of CD8⁺ T cells, partially also CD4⁺ T‐cell responses

‐ Induction of strong humoral responses, which could be induced without adjuvant in mice and non‐human primates.

However, it seems crucial to determine which antibody is used for targeting as not all induce a full‐blown immune response.