PDL-1 Antibody Drug Conjugate for Selective Chemo-Guided Immune Modulation of Cancer

Abstract

Targeting immune checkpoint molecules such as programmed death ligand-1 (PDL1) is an emerging strategy for anti-cancer therapy. However, transient expression of PDL1 and difficulty in tumor stroma penetration has limited the utility of anti-PDL1 therapy. To overcome these limitations, we report a new conjugate between the clinically approved PDL1 antibody (PDL1 AB) and drug Doxorubicin (Dox), named PDL1-Dox. We conjugated PDL1-Dox through a hydrazone linker containing a polyethylene glycol (PEG) spacer, which allows it to dissociate in a tumor environment and improves solubility. The purpose of using Dox is to disrupt the tumor extracellular environment so that PDL-1 antibody can penetrate the tumor core. PDL1-Dox demonstrates significant cell killing, disruption of tumor spheroid and induction of apoptosis in a breast cancer cell line. Significant release of IFN-γ suggests PDL1-Dox can upmodulate T cell activation. Optical imaging of dye conjugate supports the selective tumor targeting ability and core penetration of the construct.

Novel cucurmosin‐based immunotoxin targeting programmed cell death 1‐ligand 1 with high potency against human tumor in vitro and in vivo

“…It is worth noting that MDA‐MB‐231 cells are most sensitive to D‐CUS 245C , with an IC 50 value of 0.14 pmol/L, 10 7 times lower than other PD‐L1 Ab‐based conjugates; eg the IC 50 value of PDL1‐Dox 30 in MDA‐MB‐231 cells is 1.25 μmol/L. According to a report, the response of TNBC patients to PD‐1 inhibitors was relatively moderate (19%) 33 .…”

“…Immunotoxin‐based anti‐PD‐L1 mAb is considered to be an effective tumor treatment method in theory, because: (i) the immune checkpoint protein PD‐L1 is broadly expressed in many cancers, 9,20,26,27 which is spectral in treatment; (ii) its expression is limited in tumor area but not in normal cells, the treatment is mainly aimed at tumor tissue, which makes PD‐L1‐specific treatment more accurate, and its side‐effects limited; (iii) ELISA assay showed that PD‐L1, as a transmembrane protein, was not released from the constitutively expressing PD‐L1 cell membrane; and (iv) the key is that PD‐L1 on tumor cells is glycosylated, so when anti‐PD‐L1 mAb is combined in the glycosylated domain, it will produce internalization, 28 which provides a good antitumor basis for IT‐based treatment 28,29 . At present, PD‐L1‐specific treatment, such as PDL1‐Dox 30 and PD‐L1‐AuNP‐DOX 31 in the form of an Ab‐drug conjugate, have shown some promising results. However, few studies focus on the generation of PD‐L1 by ITs.…”

Antibody Conjugation of Nanoparticles as Therapeutics for Breast Cancer Treatment

“…An example would be the use of anti-PD-L1 (programmed death-ligand 1) antibodies that disrupt the inhibitory effect of the PD1/PD-L1 axis by acting on this receptor expressed in tumoral cells. A similar approach using ADCs has been recently reported [ 185 ].…”

NRXN1 as a novel potential target of antibody-drug conjugates for small cell lung cancer

“…Five ADCs have been approved by the Food and Drug Administration: brentuximab vedotin for Hodgkin lymphoma [15], ado-trastuzumab emtansine for HER2positive metastatic breast cancer [16,17], inotuzumab ozogamicin for acute lymphoblastic leukemia [18], gemtuzumab ozogamicin for CD33-positive acute myeloid leukemia [19], and trastuzumab deruxtecan for unresectable or metastatic HER2-positive breast cancer patients who have received two or more prior anti-HER2based regimens in a metastatic setting [20]. To date, ADCs targeting solid tumors other than metastatic breast cancer have not exhibited distinct clinical benefits [21][22][23][24][25][26][27][28][29]. In SCLC, DLL3, a cell surface Notch ligand that appear to be a direct downstream target of ASCL1 [30,31], has been identified as a novel target for ADCs [32].…”