Strategies to enhance monoclonal antibody uptake and distribution in solid tumors

Brandon M. Bordeau; Joseph P. Balthasar

doi:10.20892/j.issn.2095-3941.2020.0704

Article Figures & Data

Figures

Tables

Download figure
Open in new tab
Download powerpoint
Figure 1
Shown is a graphic representation of barriers that limit therapeutic antibody uptake and distribution into solid tumors and the approaches that have been reported to mitigate the tumor barriers. A graphic key is provided in the bottom left inset. Figure 1 was created using BioRender.com.

Tables

Figures

View popup

Table 1

FDA approved mAbs for solid tumor indications

Antibody (mAb)	Format	Indication	Target	Year approved	Trial	Trial arm	Comparator	Notes
Trastuzumab (Herceptin)	Humanized IgG1 mAb	Breast cancer	HER2	1998	mAb + chemotherapy vs. chemotherapy	MTP: 7.2 months ORR: 45% DOR: 8.3 months 1-year survival: 79%	MTP: 4.5 months ORR: 29% DOR: 5.8 months 1-year survival: 68%	Approved in combination with paclitaxel for patients without prior chemotherapy or as a single agent in patients who have progressed on chemotherapy
Cetuximab (Erbitux)	Chimeric IgG1 mAb	Colorectal cancer	EGFR	2004	mAb + irinotecan vs. mAb	ORR: 22.9% MTP: 4.1 months	ORR: 10.8% MTP: 1.5 months	Assessed in patients who progressed on irinotecan. Approved in combination with irinotecan for patient’s refractory to irinotecan or as a single agent for patients intolerant to irinotecan
Bevacizumab (Avastin)	Humanized IgG1	Colorectal cancer	VEGF	2004	mAb + IFL vs. IFL + placebo	MTP: 20.3 months PFS: 10.6 months ORR: 45% DOR: 10.4 months	MTP: 15.6 months PFS: 6.4 months ORR: 35% DOR: 7.1 months	Tested in combination with 5-fluorouracil, irinotecan, leucovorin
Panitumumab (Vectibix)	Humanized IgG2 mAb	Colorectal cancer	EGFR	2006	mAb + best supportive care vs. best supportive care	PFS: 96 days ORR: 8%	PFS: 60 days ORR: 0%	Assessed in patients who progressed on fluoropyrimidine, oxaliplatin, and irinotecan. No difference in overall survival observed
Pertuzumab (Perjeta)	Humanized IgG1	Breast cancer	HER2	2012	mAb + trastuzumb + docetaxel vs. placebo + trastuzumab + docetaxel	PFS: 18.5 months ORR: 80.2% DOR: 20.2 months Survival: 82.8%	PFS: 12.4 months ORR: 69.3% DOR: 12.5 months Survival: 76.4%	Approved in combination with trastuzumab and docetaxel for patients who have not received prior therapy
Ado-trastuzumab emtansine (Kadcyla)	Humanized IgG1 ADC	Breast cancer	HER2	2012	ADC vs. lapatinib + capecitabine	PFS: 9.6 months ORR: 43.6% DOR: 12.6 months MS: 30.9 months	PFS: 6.4 months ORR: 30.8% DOR: 6.5 months MS: 25.1 months	Tested in patients with metastatic or locally advanced breast cancer with prior trastuzumab or prior taxane therapy
Ramucirumab (Cyramza)	Human IgG1	Gastric cancer	VEGFR2	2014	mAb + best supportive care vs. best supportive care + placebo	PFS: 2.1 months MS: 5.2 months	PFS: 1.3 months MS: 3.8 months	Tested in patients with locally advanced or metastatic gastric cancer who previously received platinum or fluoropyrimidine chemo
Nivolumab (Opdivo)	Human IgG4	Melanoma/NSCLC	PD1	2014	Single-arm trial	ORR: 32%	N/A	Tested in patients with unresectable or metastatic melanoma that progressed on ipilimumab
Pembrolizumab (Keytruda)	Humanized IgG4	Melanoma	PD1	2014	Single-arm trial	ORR: 24%	N/A	Tested in patients with unresectable or metastatic melanoma that progressed on ipilimumab
Necitumumab (Portrazza)	Human IgG1	NSCLC	EGFR	2015	mAb + gemcitabine + cisplatin vs. gemcitabine + cisplatin	PFS: 5.7 months OS: 23%ORR: 31% MS: 11.5 months	PFS: 5.5 months OS: 19%ORR: 29% MS: 9.9 months	Tested as a first line chemotherapy in patients with metastatic squamous NSCLC
Dinutuximab (Unituxin)	Chimeric IgG1	Neuroblastoma	GD2	2015	mAb + RA vs. RA	OS: 73% EFS: 71%	OS: 58% EFS: 56%	Tested in pediatric patients with high risk neuroblastoma. “RA = 13-cis-retinoic acid”
Olaratumab (Lartruvo)	Human IgG1	Soft tissue sarcoma	PDGFR-alpha	2016	mAb + doxorubicin vs. doxorubicin	OS: 41% MS: 26.5 months PFS: 8.2 months ORR: 18.2%	OS: 22% MS: 14.7 months PFS: 4.4 months ORR: 7.5%	Eligible patients were required to have soft tissue sarcoma not amenable to curative treatment with surgery or radiotherapy, a histologic type of sarcoma for which an anthracycline-containing regimen was appropriate but had not been administered
Atezolizumab (Tecentriq)	Humanized IgG1	Bladder cancer	PD-L1	2016	Single-arm trial	ORR: 14.8%	N/A	Tested in patients with locally advanced or metastatic urothelial carcinoma that progressed on platinum containing chemotherapy.
Avelumab (Bavencio)	Human IgG1	Merkel cell carcinoma	PD-L1	2017	Single-arm trial	ORR: 33%	N/A	Tested in patients who progressed on chemotherapy for distant metastatic disease
Durvalumab (IMFINZI)	Human IgG1	Bladder cancer	PD-L1	2017	Single-arm trial	ORR: 17%	N/A	Tested in patients with metastatic urothelial cancer that progressed on or after a platinum-based therapy
Cemiplimab (Libtayo)	Human mAb	Cutaneous squamous cell carcinoma	PD-1	2018	Single-arm trial	ORR: 47.2%	N/A	Tested in patients with metastatic or locally advanced CSCC that were not candidates for curative surgery or radiation
Enfortumab vedotin (Padcev)	Human IgG1 ADC	Urothelial cancer	Nectin-4	2019	Single-arm trial	ORR: 44% DOR: 7.6 months	N/A	Tested in patients with locally advanced or metastatic urothelial cancer with prior PD-1 or platinum-based chemo
[fam-]trastuzumab deruxtecan-nxki (Enhertu)	Humanized IgG1 ADC	Metastatic breast cancer	HER2	2019	Single-arm trial	ORR: 60.3% DOR: 14.8 M	N/A	Tested in patients with HER2-positive, unresectable and/or metastatic breast cancer who had received 2 or more prior anti-HER2 therapies
Sacituzumab govitecan-hziy (Trodelvy)	Humanized IgG1 ADC	Triple-neg. breast cancer	TROP-2	2020	Single-arm trial	ORR: 33.3% DOR: 7.7 M	N/A	Tested in patients with metastatic triple negative breast cancer who progressed on 2 prior treatments.

mAb, antibody; ADC, antibody drug conjugate; OS, overall survival; PFS, progression-free survival; ORR, objective response rate; MS, median survival; DOR, median duration of response; EFS, event-free survival.

View popup

Table 2

Vasculature modulation approaches

Treatment	Impact on tumor	Impact on mAb tumor PK	mAb/tumor model	Source
Bevacizumab	Decrease in tumor vasculature and permeability	63% decrease in AUC (0–10 days)	T84.66 LS174T	²⁸
Sorafenib	Decrease in tumor vasculature and permeability	41% decrease in AUC (0–7 days)	T84.66 LS174T	¹³¹
Angiotensin II	Increase in trans vascular pressure gradient, enhanced tumor blood flow	40% increase in uptake 4 h after administration	CC49 LS174T	⁴¹
TNF-alpha administered intravenously (IV) or intra-tumorally (IT)	Enhanced vasopermeability	(IT) 200% increase at 3 h, 27% increase at 22 h (IV) 100% increase at 3 h	Mab35 LOVO	⁴²
Interferon	Enhanced blood flow	83% increase in uptake 1.5 h after administration	MEM136 WM-9	⁴³
Interleukin 2 conjugate	Enhanced vasopermeability	275% increase in uptake 3 days after administration	TNT-1 F(ab′)2 ME-180	⁴⁵
TNF-alpha conjugate	Enhanced vasopermeability and blood flow	213% increase in uptake 3 days after administration	TNT-1 F(ab′)2 ME-180	⁴⁵
Interleukin 1 conjugate	Enhanced vasopermeability and blood flow	200% increase in uptake 3 days after administration	TNT-1 F(ab′)2 ME-180	⁴⁵
Leukotriene-B4 conjugate	Enhanced blood flow	122% increase in uptake 3 days after administration	TNT-1 F(ab′)2 ME-180	⁴⁵
Histamine conjugate	Enhanced vasopermeability	118% increase in uptake 3 days after administration	TNT-1 F(ab′)2 ME-180	⁴⁵
Physalaemin conjugate	Enhanced blood flow	71% increase in uptake 3 days after administration	TNT-1 F(ab′)2 ME-180	⁴⁵
Bradykinin conjugate	Enhanced blood flow	23% increase in uptake 3 days after administration	TNT-1 F(ab′)2 ME-180	⁴⁵
PEP2-Ab conjugate	Enhanced vasopermeability	249% increase in uptake 3 days after administration	B72.3 LS174T	⁴⁶
A22p-Ab conjugate	Enhanced vasopermeability	50%–100% increase in uptake at 3 and 12 h after administration	Cetuximab/A459 Trastuzumab/SKOV3	⁴⁹
iRGD	Enhanced vasopermeabiltiy	3,900% Increase at 3 h by ELISA	Trastuzumab BT-474	⁴⁸
Mannitol Infusion	Osmotic opening of BBB	234% and 32% increase in F(ab′)2 and mAb AUC (0.5–72 h)	P1.17 LX-1 SCLC	⁵⁸
Focused ultrasound	Transient disruption of BBB	5,577% increase in uptake 2 h after administration	Bevacizumab U87 glioma	⁶³
Angiopep-2-Ab conjugate	RMT through BBB by LRP1 binding	˜300% increase in tumor uptake 24 h after administration	Trastuzumab BT-474	⁶⁸
Human melanotransferrin-Ab conjugate	RMT through BBB by LRP1 binding	415% increase in tumor uptake 2 h after administration	Trastuzumab MDA-MB-231-BR^HER2/eGFP	⁶⁹

View popup

Table 3

Extracellular matrix modulation approaches

Treatment	Impact on tumor	Impact on mAb tumor PK	mAb/tumor model	Source
Intratumoral collagenase	Collagen degradation	80%–100% increase in diffusion 24 h after collagenase injection	Non-specific IgG (S1) HSTS-26T and U87	⁷⁷
Intravenous collagenase	Collagen degradation/decrease in tumor interstitial fluid pressure	90%–140% increase in uptake at 24 h	TP-3 OHS	⁷⁹
Relaxin infusion	Downregulation of tumor fibrosis/decrease collagen fiber length and signal	80% increase in diffusion coefficient after a 12-day relaxin infusion	Non-specific IgG HSTS-26T	⁷⁸
Intratumoral injection of bovine hyaluronidase	Hyaluronan degradation/decrease in interstitial fluid pressure	70% increase in uptake 9 days after administration	TP-3 OHS	⁸⁰
Pegylated human hyaluronidase (PEGPH20)	Tumor hyaluronan degradation	100% increase in uptake 2 days after administration	Trastuzumab SKOV3-HAS2	⁸²
Pulsed ultrasound	Structural modification of extracellular matrix and widening of intercellular gaps	36% Increase in tumor AUC (0–5 days)	MX-B3 A431	¹³⁰

View popup

Table 4

Antigen and cellular modulation approaches

Approach	Impact on mAb tumor PK	mAb/tumor model	Source
pH sensitive mAb	30% increase in tumor AUC (0–14 days) in comparison to non-pH sensitive mAb T84.66	10H6/T84.66 MC38CEA+	¹²⁶
Paclitaxel administered 2 days after mAb administration	30% increase in cumulated activity 0–6 days	¹¹¹In-DOTA-Gly3Phe-m170/breast or prostate cancer	¹⁰⁶
5-fluorouracil treatment 2 days prior to mAb administration	148% increase in uptake 5 days after administration	¹²⁵I-NHS76 Colon 26	¹⁰⁷
Paclitaxel treatment 2 days prior to mAb administration	102% increase in uptake 5 days after administration	¹²⁵I-NHS76 Colon 26	¹⁰⁷
Tofacitinib	48% increase (LMB) and 133% increase (BV421) in tumor cell uptake/binding 3 h after administration	LMB-100/KLM-1 BV421/MDA-MB-461	¹⁰⁸
Junction opener 1	500% increase in tumor uptake 12 h after administration	Trastuzumab HCC1954	¹⁰⁹