Leading Edge: Intratumor Delivery of Monoclonal Antibodies for the Treatment of Solid Tumors
Abstract
:1. Therapeutic Antibodies: Beyond Conventional Monoclonal Antibodies (mAbs)
2. In Vivo mAb Gene Delivery Systems
3. Routes of mAbs Administration
4. Intratumor mAbs Delivery in Solid Tumors
5. Preclinical Non-Viral Vectors for mAbs Intratumor Delivery
5.1. Nanoparticles and Lipid Vesicles
5.2. Microneedle Delivery Platforms
5.3. Hydrogels as Delivery Vehicles
5.4. HSC−Platelet−Anti-PD-1 Assembly
5.5. Intratumor Plasmid DNA (pDNA) Electroporation
5.6. Antigen Peptides Conjugated on mAbs
6. Intratumor Delivery of mAbs with Viral Vectors in Preclinical Models
6.1. Oncolytic Viruses for the Treatment of Solid Tumors
6.2. Semliki Forest Virus (SFV)
6.3. Adeno-Associated Viral Vectors
6.4. Adenovirus Vectors
7. Intratumor mAbs Delivery under Clinical Development
8. Selected Clinical Trials According to Therapy Types
8.1. Clinical Trials with Administration of Conventional Monoclonal Antibodies
8.2. Clinical Trials with Oncolytic Viruses
8.3. Clinical Trials with Non-Viral Lipid Nanoparticles
9. Key Notes and Conclusions
- The use of conventional mAbs is limited by their complex structure. Novel designs such as bispecific antibodies or nanobodies can be good alternatives.
- Direct in vivo delivery of synthetic nucleic acids encoding antibodies such as plasmid DNA or mRNA platforms represent new approaches for in vivo delivery of antibody-like biologics. These platforms have advantages such as rapid product development and simpler manufacturing processes.
- Intratumor delivery increases efficacy, local bioavailability, reduces toxicity, and improves the antitumor immune responses.
- Intratumor delivery can be combined with other systemic strategies and can be implemented with non-viral- and viral-based delivery methods, including nanoparticles or lipid vesicles.
- Virotherapies are promising approaches for cancer treatment and as delivery vehicles of mAbs, but may pose biosafety concerns, especially for the use of oncolytic viruses.
10. Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Drug Name (s) | Format | Target (s) | Type of Cancer | Current Status | ClinicalTrials.gov Identifier | Nº Participants | FDA Approval Status |
---|---|---|---|---|---|---|---|
KN046 | Tetravalent, bispecific, Fc-fusion protein | CTLA-4, PD-L1 | Advanced solid tumors and lymphoma | Phase II/III | NCT03872791 | 52 | No |
NCT04474119 | 482 | No | |||||
NCT04925947 | 29 | FDA-regulated Drug Product | |||||
Envolimab KN035 | Monospecific, Fc-fusion protein | PD-L1 | Advanced solid tumors, multiple primary neoplasm | Phase II | NCT03667170 | 200 | No |
NCT04182789 | 20 | No | |||||
NCT04891198 | 200 | No | |||||
αPD1-MSLN-CAR T cells | single-chain variable fragments (scFv) | αPD1-MSLN-CAR T | MSLN-positive Advanced Solid Tumors | Early phase I | NCT05373147 | 21 | No |
INBRX-109 | Tetravalent, monospecific, | Death receptor 5 | Advanced solid tumors, conventional chondrosarcoma | Phase I/II | NCT03715933 | 240 | FDA-regulated Drug Product |
Fc-fusion protein | NCT04950075 | 201 | FDA-regulated Drug Product | ||||
KN044 | Monospecific, Fc-fusion protein | CTLA-4 | Advanced solid tumors | Phase I | NCT04126590 | 39 | FDA-regulated Drug Product |
Target (s) | Delivery | Type of Cancer | Current Status | ClinicalTrials.gov Identifier | Nº Participants | FDA Approval Status |
---|---|---|---|---|---|---|
PD-1 | Intravenous infusion | Advanced gastric adenocarcinoma | Phase II | NCT03704246 | 123 | No |
Intravenous injection | Gastric cancer | Phase I | NCT03713905 | 400 | No | |
Intravenous injection | Colorectal cancer. | Phase I/ II | NCT03711058 | 54 | FDA-regulated Drug Product | |
Intravenous infusion | Advanced Solid Tumors | Phase I/ II | NCT04775680 | 60 | No | |
Intravenous injection | Gastric cancer | Phase II | NCT03704246 | 123 | No | |
Intravenous injection | Advanced solid tumors | Phase I | NCT04478461 | 21 | No | |
Intravenous injection | Advanced refractory solid tumors. | Phase I | NCT02791334 | 215 | FDA-regulated Drug Product | |
PD-1/TIM-3 Bispecific Antibody | Intravenous injection | Advanced and/or metastatic solid tumors | Phase I | NCT03708328 | 134 | FDA-regulated Drug Product |
Anti-CD47/PD-1 Bifunctional Antibody | Intravenous injection | Advanced solid tumors | Phase II | NCT04886271 | 210 | No |
PD-1/VEGF Bispecific Antibody | Intravenous infusion | Solid tumors | Phase I/ II | NCT04597541 | 59 | No |
PD-1/CTLA-4 Bispecific Antibody | Intravenous injection | Advanced or metastatic solid tumors | Phase I/ II | NCT03852251 | 338 | No |
PD-1 formulated with MK-5180 | Subcutaneous Injection | Advanced Solid Tumors | Phase I | NCT05017012 | 72 | No |
CTLA-4 | Intravenous injection | Advanced Solid Tumors | Phase I | NCT03849469 | 242 | FDA-regulated Drug Product |
CD39 | Intravenous infusion | Locally advanced or metastatic solid tumors | Phase I | NCT05075564 | 60 | FDA-regulated Drug Product |
OX40 | Intratumoral or intravenous injection | Advanced solid tumors | Phase I | NCT03831295 | 12 | FDA-regulated Drug Product |
LAG3 | Intravenous injection | Advanced solid tumors | Phase I/ II | NCT01968109 | 1499 | FDA-regulated Drug Product |
CCR5 | Subcutaneous Injection | Locally advanced or metastatic solid tumors | Phase II | NCT04504942 | 30 | FDA-regulated Drug Product |
4-1BB | Intravenous infusion | Advanced Solid Malignancies | Phase I | NCT04144842 | 50 | No |
PD-L1xCD27 Bispecific Antibody | Intravenous infusion | Advanced Solid Malignancies | Phase I | NCT04440943 | 27 | FDA-regulated Drug Product |
PD-L1 | Intravenous infusion | Advanced Solid Malignancies | Phase I | NCT03590054 | 35 | FDA-regulated Drug Product |
Anti-PD-L1/Anti-CTLA4 | Intravenous injection | Advanced Solid Malignancies | Phase I/II | NCT03518606 | 150 | No |
Target | Non i.t /co-i.t Therapy | Type of Cancer | ClinicalTrials.gov Identifier | Nº Participants | FDA Approval Status | |
---|---|---|---|---|---|---|
CTLA-4 | Injection of ipilimumab during a biopsy procedure. | Head and neck Cancer | NCT02812524 | 18 | FDA-regulated Drug Product | |
Combination with intravenous nivolumab | Melanoma | NCT02857569 | 90 | Not provided | ||
Combination with intravenous nivolumab | Glioblastoma | NCT03233152 | 6 | No | ||
Intratumoral Tilsotolimod combination with intratumoral ipilimumab and intravenous nivolumab. | Advanced cancers | NCT04270864 | 72 | No | ||
PD-1 | mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L, IL-23, and IL-36γ. | Ductal Carcinoma in Situ (DCIS) | NCT02872025 | 48 | FDA-regulated Drug Product | |
Intra-lesional nivolumab therapy | Cutaneous Kaposi Sarcoma | NCT03316274 | 12 | FDA-regulated Drug Product | ||
Pre-operative cemiplimab administered intralesionally | Cutaneous Squamous Cell Carcinoma | NCT03889912 | 61 | FDA-regulated Drug Product | ||
Combination of PD-1 and CTLA4 | Metastatic Prostatic Adenocarcinoma | NCT04090775 | 12 | FDA-regulated Drug Product | ||
mAbs delivery and | CD40 | Alone intratumorally or intravenously administered ADC-1013 | Advanced Solid Tumors | NCT02379741 | 24 | Not provided |
non-viral theraphy | APX005M in Combination with systemic prembrolizumab | Metastatic Melanoma | NCT02706353 | 41 | FDA-regulated Drug Product | |
ABBV-927 and ABBV-181 | Advanced solid tumors | NCT02988960; NCT03818542 | 163;3 | FDA-regulated Drug Product | ||
Intratumoral Selicrelumab with atezolizumab | Relapsed B Cell Lymphoma | NCT03892525 | 4 | No | ||
Fc-engineered anti-CD40 agonist | Lesions to the Skin | NCT04059588 | 28 | FDA-regulated Drug Product | ||
SL-172154: fusion protein SIRPα-Fc-CD40L | Squamous Cell Carcinoma: Head and Neck or Skin | NCT04502888 | 5 | FDA-regulated Drug Product | ||
D2C7-IT in Combination With 2141-V11 | Malignant Glioma | NCT04547777 | 30 | FDA-regulated Drug Product | ||
Intratumoral TriMix Injections (CD40 and CD27) | Breast Cancer Patients | NCT03788083 | 36 | No | ||
OX40 | mRNA 2416 alone or in combination with durvalumab | Advanced Malignancies | NCT03323398 | 79 | FDA-regulated Drug Product | |
Combinaiton with TLR9 agonist SD-101 and radiation | Low-Grade B-Cell Non-Hodgkin Lymphomas | NCT03410901 | 15 | FDA-regulated Drug Product | ||
CD137 | Urelumab combined with nivolumab | Solid Tumors | NCT03792724 | 32 | Product Manufactured in and Exported from the U.S | |
CD40 | MEM-288:oncolytic adenovirus vector encoding transgenes for human IFNβ and a recombinant chimeric form of CD40-ligand | Solid tumors | NCT05076760 | 18 | FDA-regulated Drug Product | |
CD40 | AdCD40L is a replication-deficient virus carrying the gene for CD40 ligand | Melanoma | NCT01455259 | 30 | Not provided | |
Viral therapy | PD-1 | MVR-C5252: oncolytic vectors expressing IL-12 and anti-PD-1 antibody | Recurrent or progressive glioblastoma | NCT05095441 | 51 | FDA-regulated Drug Product |
PD-1 | ONCOS-102: Oncolytic Adenovirus Expressing GMCSF and combined with prembrolizumab | Melanoma progressing after (PD1) Blockade | NCT03003676 | 21 | Not provided | |
CTLA-4 | ISI-JX: Pexa-Vecan oncolytic virus genetically modified to express GM-CSF with intratumoural administration of ipilimumab | Advanced /solid tumors | NCT02977156 | 22 | Not provided | |
PD-1 and CTLA-4 | ONCR-177 (which encodes CCL4, IL-12, Flt3L, anti-CTLA-4, anti-PD1alone or combined with pembrolizumab | Advanced/metastatic solid tumors | NCT04348916 | 132 | FDA-regulated Drug Product |
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Blanco, E.; Chocarro, L.; Fernández-Rubio, L.; Bocanegra, A.; Arasanz, H.; Echaide, M.; Garnica, M.; Piñeiro-Hermida, S.; Kochan, G.; Escors, D. Leading Edge: Intratumor Delivery of Monoclonal Antibodies for the Treatment of Solid Tumors. Int. J. Mol. Sci. 2023, 24, 2676. https://doi.org/10.3390/ijms24032676
Blanco E, Chocarro L, Fernández-Rubio L, Bocanegra A, Arasanz H, Echaide M, Garnica M, Piñeiro-Hermida S, Kochan G, Escors D. Leading Edge: Intratumor Delivery of Monoclonal Antibodies for the Treatment of Solid Tumors. International Journal of Molecular Sciences. 2023; 24(3):2676. https://doi.org/10.3390/ijms24032676
Chicago/Turabian StyleBlanco, Ester, Luisa Chocarro, Leticia Fernández-Rubio, Ana Bocanegra, Hugo Arasanz, Miriam Echaide, Maider Garnica, Sergio Piñeiro-Hermida, Grazyna Kochan, and David Escors. 2023. "Leading Edge: Intratumor Delivery of Monoclonal Antibodies for the Treatment of Solid Tumors" International Journal of Molecular Sciences 24, no. 3: 2676. https://doi.org/10.3390/ijms24032676