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G. Yang and Y. Huang
6.5.2.3 NOX-A12 Targeting CXCL-12
NOX-A12 [252, 253] is a 45-nt L-form RNA aptamer known as a Spiegelmer, developed against chemokine (C-X-C motif) ligand 12 (CXCL-12). Also known as stromal
cell-derived factor-1 (SDF-1) [15, 163, 254], CXCL-12 plays important roles in tumor
proliferation, new blood vessel formation, and metastasis. It has two types of binding
sites, both of which are targets of therapeutic intervention. By binding to these two key
sites, NOX-A12 disrupts CXCL-12 activity and modulates the tumor microenvironment to fight tumors, including multiple myeloma and solid tumors (lung, colorectal,
and brain cancer). NOX-A12 was developed by NOXXON. Spiegelmers are mirrorimage oligonucleotides that cannot be recognized by nucleases, and thus display high
biostability in the bloodstream/human serum. In phase 1 studies, NOX-A12 had a
favorable safety profile when administered IV to healthy individuals [60]. Currently,
NOX-A12 is being evaluated in two phase 2 clinical trials in combination with either
chemoimmunotherapy (bendamustine and rituximab) in patients with relapsed CLL
[49], or bortezomib (proteasome inhibitor) and dexamethasone (corticosteroid) in
patients with relapsed multiple myeloma [50].
6.5.2.4 Targeting PD-1/PD-L1
Programmed cell death 1 (PD-1; also known as CD279) is expressed in several
cell types including T-lymphocytes, specifically CD8 tumor-infiltrating lymphocytes,
which are in charge of directly eradicating tumor cells [255]. The interaction between
PD-1 expressed on the surface of T-lymphocytes and PD-L1 expressed on cancer cells
leads to an impairment of CD8 cytotoxicity. Prodeus et al. developed a 40 kDa PEGylated DNA aptamer, PEG-MP7, that specifically binds to PD-1, decreases tumor
growth, and increases survival in mouse tumor models [256]. Their study found that
PD-L1-mediated suppression of IL-2 secretion was functionally inhibited in primary
T-cells treated with the base aptamer MP7 or a known anti-PD-1 antibody, but not
control aptamer. Furthermore, an in vivo study using a murine colon cancer model
(MC38 cells stably expressing human CEA; MC38.CEA) showed that PEG-MP7
effectively inhibited PD-1/PD-L1 interaction, showing efficacy equal to anti-PD-1
antibody in suppressing PD-L1+ carcinoma cell growth. Additional study by Lai
et al. reported the PD-L1 antagonizing DNA aptamer (aptPD-L1) for the blockade of
the binding between human PD-1 and PD-L1 [257]. Repeated intraperitoneal administrations of aptPD-L1 (1.2 mg/kg, 4 times a week) led to significant tumor growth
inhibition compared to random-sequence aptamer administration in both the CT26
colon cancer cell line and LL/2 Lewis lung cancer cell line murine syngeneic tumor
model mice.
G. Yang and Y. Huang
6.5.2.3 NOX-A12 Targeting CXCL-12
NOX-A12 [252, 253] is a 45-nt L-form RNA aptamer known as a Spiegelmer, developed against chemokine (C-X-C motif) ligand 12 (CXCL-12). Also known as stromal
cell-derived factor-1 (SDF-1) [15, 163, 254], CXCL-12 plays important roles in tumor
proliferation, new blood vessel formation, and metastasis. It has two types of binding
sites, both of which are targets of therapeutic intervention. By binding to these two key
sites, NOX-A12 disrupts CXCL-12 activity and modulates the tumor microenvironment to fight tumors, including multiple myeloma and solid tumors (lung, colorectal,
and brain cancer). NOX-A12 was developed by NOXXON. Spiegelmers are mirrorimage oligonucleotides that cannot be recognized by nucleases, and thus display high
biostability in the bloodstream/human serum. In phase 1 studies, NOX-A12 had a
favorable safety profile when administered IV to healthy individuals [60]. Currently,
NOX-A12 is being evaluated in two phase 2 clinical trials in combination with either
chemoimmunotherapy (bendamustine and rituximab) in patients with relapsed CLL
[49], or bortezomib (proteasome inhibitor) and dexamethasone (corticosteroid) in
patients with relapsed multiple myeloma [50].
6.5.2.4 Targeting PD-1/PD-L1
Programmed cell death 1 (PD-1; also known as CD279) is expressed in several
cell types including T-lymphocytes, specifically CD8 tumor-infiltrating lymphocytes,
which are in charge of directly eradicating tumor cells [255]. The interaction between
PD-1 expressed on the surface of T-lymphocytes and PD-L1 expressed on cancer cells
leads to an impairment of CD8 cytotoxicity. Prodeus et al. developed a 40 kDa PEGylated DNA aptamer, PEG-MP7, that specifically binds to PD-1, decreases tumor
growth, and increases survival in mouse tumor models [256]. Their study found that
PD-L1-mediated suppression of IL-2 secretion was functionally inhibited in primary
T-cells treated with the base aptamer MP7 or a known anti-PD-1 antibody, but not
control aptamer. Furthermore, an in vivo study using a murine colon cancer model
(MC38 cells stably expressing human CEA; MC38.CEA) showed that PEG-MP7
effectively inhibited PD-1/PD-L1 interaction, showing efficacy equal to anti-PD-1
antibody in suppressing PD-L1+ carcinoma cell growth. Additional study by Lai
et al. reported the PD-L1 antagonizing DNA aptamer (aptPD-L1) for the blockade of
the binding between human PD-1 and PD-L1 [257]. Repeated intraperitoneal administrations of aptPD-L1 (1.2 mg/kg, 4 times a week) led to significant tumor growth
inhibition compared to random-sequence aptamer administration in both the CT26
colon cancer cell line and LL/2 Lewis lung cancer cell line murine syngeneic tumor
model mice.