ABSTRACT
Twenty-five years after their advent, monoclonal antibodies (MAbs) have emerged as an important and rapidly expanding new drug class for the treatment of severe human diseases (1–3). Ten antibodies have been approved in the United States for diverse clinical indications: cancer, transplant rejection, Crohn’s disease, respiratory syncytial virus (RSV) prophylaxis, and as an anti-thrombotic (Table 1). An additional 70 or so antibody therapeutics are in clinical trials in the United States including at least 46 that have progressed to phase I/II or farther (Table 2). This chapter focuses on recent developments with antibody therapeutics from a biotechnology perspective. Antibodies Approved for Therapeutic Use in the United States https://www.niso.org/standards/z39-96/ns/oasis-exchange/table">
Product, antibody name
Technology
Antibody format
Antigen
Indication
Company
Worldwide 2000 sales a ($M3)
Orthoclone OKT3, muromonab-CD3
Murine
IgG2a
CD3
Prevention of acute kidney, heart, and liver transplant rejection
Ortho Biotech
ReoPro, abciximab
Chimeric
Fab
gpIIbIIIa
Prevention of platelet-mediated clots in coronary angioplasty
Centocor
418
Rituxan, rituximab
Chimeric
IgG1
CD20
Non-Hodgkin’s lymphoma
IDEC, Genentech
424
Simulect, basiliximab
Chimeric
IgG1
CD25 b
Prevention of acute kidney transplant rejection
Novartis
Remicade, infliximab
Chimeric
IgG1
TNFα
Crohn’s disease
Centocor
57
Zenapax, daclizumab
Humanized
IgG1
CD25 b
Prevention of acute kidney transplant rejection
Hoffman-La Roche
Synagis, palivizumab
Humanized
IgG1
RSV F glyco-protein
Prophylaxis of RSV in high-risk pediatric patients
MedImmune
427
Herceptin, trastuzumab
Humanized
IgG1
HER2/neu antigen
Metastatic breast cancer overexpressing HER2/neu
Genentech
276
Mylotarg, gemtuzumab ozogamicin
Humanized, calecheamicin conjugate
IgG4
CD33
CD33-positive acute myeloid leukemia
Wyeth Laboratories
Campath, alemtuzumab
Humanized
IgG1
CD52
B-cell chronic lymphocytic leukemia
Millennium & ILEX Partners, distributed by Berlex Laboratories
(approved 5/01)
Sales data were obtained from company websites or by searching for “drugname 2000 sales” with search engine www.google.com.
CD25 is the Tac subunit of the interleukin 2 receptor.
Source: Refs. 1,3,179,180, and company websites. Antibody-Derived Therapeutic Agents in Advanced Clinical Trials in the United States<xref ref-type="fn" rid="tbl20_2_1"> <sup>a</sup> </xref> https://www.niso.org/standards/z39-96/ns/oasis-exchange/table">Antibody name
Core technology
Antibody format
Enhancement technology
Target
Proposed use
Development stage
Sponsor
ABX-IL8
Human
IgG2
IL-8
Psoriasis, chronic obstructive pulmonary disease
Phase II, Phase IIa
Abgenix
HuMax-CD4
Human
IgG1
CD4
Rheumatoid arthritis, psoriasis
Phase II
Genmab A/S
ABX-EGF
Human
IgG2
EGFR
Renal cancer
Phase II
Immunex, Abgenix
Xolair, omalizumab
Humanized
IgG1
IgE
Allergic rhinitis, allergic asthma
BLA filed with FDA
Genentech, Novartis, Tanox Biosystems
Zamyl, SMART M195
Humanized
IgG1
CD33
Acute myeloid leukemia
Phase III
Protein Design Labs
Xanelim, efalizumab
Humanized
IgG1
CD11a
Psoriasis
Phase III
Genentech, XOMA
Avastin, bevacizumab rhuMAb-VEGF
Humanized
IgG1
VEGF
Metastatic non–small-cell lung, colorectal
Phase III
Genentech
LymphoCide, epratuzumab
Humanized
IgG
CD22
Non-Hodgkin’s lymphoma
Phase III
Immunomedics
Remitogen, SMART 1D10
Humanized
IgG1
HLA-DR
Non-Hodgkins lymphoma
Phase II
Protein Design Labs
Humicade, CDP571
Humanized
IgG4
TNFα
Crohn’s disease
Phase IIb
Celltech
MDX-33 (H22)
Humanized
IgG1
CD64 (FcγRI)
Idiopathic thrombocytopenia purpura
Phase II
Aventis Behring, Medarex
SCH5570
Humanized
IgG
IL-5
Asthma
Phase II
Schering Plough, Celltech
CEA-Cide, labetuzumab
Humanized
IgG
90Y
CEA
Colorectal cancer
Phase I/II
Immunomedics
Antegren natalizumab
Humanized
IgG
VLA-4 (α4β1 integrin) and α4β7 integrin
Multiple sclerosis, Crohn’s disease
Phase III
Elan, Biogen
MEDI-507, siplizumab
Humanized
IgG1
CD2
Psoriasis, graft-versushost disease
Phase II
MedImmune
HuMax-IL15
Human
IgG1
IL-15
Rheumatoid arthritis
Phase I/II
Genmab A/S, Immunex
Adalimumab, D2E7
Human
?
TNFα
Rheumatoid arthritis
Phase II
Abbott Laboratories
LDP-02
Humanized
IgG
α4β7 integrin
Crohn’s disease
Ulcerative colitis
Phase II
Phase I/II
Millennium
Orthoclone OKT4A
Humanized
IgG
CD4
CD4-mediated autoimmune diseases, transplant rejection
Phase II
Ortho Biotech
YM-337
Humanized
IgG
Gp IIbIIIa
Cardiovascular disorders
Phase II
Yamanouchi, Protein Design Labs
Anti-IL-4
Humanized
IgG1
IL-4
Asthma
Phase I/II
Protein Design Labs
h5G1.1
Humanized
IgG
C5
Membranous nephritis, rheumatoid arthritis
Phase II
Alexion
IDEC-131
Humanized
IgG
CD40 ligand
Immune thrombocytopenic purpura
Phase II
IDEC, Eisai
Hu-901
Humanized
IgG
IgE
Peanut-induced anaphylaxis
Phase I/II
Tanox
SMART anti-gamma interferon
Humanized
IgG1
IFN-γ
Crohn’s disease
Phase I/II
Protein Design Labs
Nuvion, SMART anti-CD3
Humanized
IgG2
CD3
Psoriasis
Phase II
Protein Design Labs
SMART anti-L-selectin
Humanized
IgG4
L-selectin
Trauma
Phase II
Protein Design Labs, licensed in Europe to Scil Biomedicals GmbH
MDX-447
Humanized × humanized
F(ab’)2
Bispecific
EGFR × CD64
Head, neck, brain, breast, and bladder cancers
Phase II
Immuno-Designed Molecules, Merck KGaA
Primatized-IDEC-151, clenoliximab
Primatized b
IgG1
CD4
Rheumatoid arthritis
Phase II
IDEC
IDEC-114
Primatized b
?
CD80
Psoriasis
Phase II
IDEC
IMC-C225, centuximab
Chimeric
IgG
EGFR
Colorectal cancer
BLA filing inprogress
ImClone Systems, Bristol-Myers Squibb Co.
Cotara, 131I-chTNT-1/B
Chimeric
IgG1
131I
DNA, histones
Recurrent glioblastoma multiforme
Phase III
Peregrine Pharmaceuticals
OvaRex, B43.13
Murine
IgG1
Antibody modification by photo-activation
CA125
Ovarian adenocarcinoma
Plan to file BLA by end of 2001
AltaRex
BrevaRex
Murine
?
Antibody modification by photoactivation
PEM
Multiple myeloma
Phase I/II
AltaRex
Bexxar, 131I tositumomab
Murine
IgG2a
131I
CD20
Non-Hodgkin’s lymphoma
BLA filed with FDA
Corixa
Zevalin, IDEC-Y2B8, 90Y ibritumomab tiuxetan
Murine
IgG1
90Y
CD20
Non-Hodgkin’s lymphoma
BLA filed with FDA
IDEC
BEC2
Murine
IgG
Anti-idiotype GD3 mimic
Small-cell lung cancer, malignant melanoma
Phase III
Phase II
ImClone Systems, Merck KGaA
Theragyn, pemtumomab
Murine
IgG1
90Y
PEM
Ovarian cancer, gastric carcinoma
Phase III
Phase II
Antisoma
Panorex, edrecolomab
Murine
IgG2a
EpCam
Colorectal cancer
Phase III
GlaxoSmithKline, Centocor,
Segard, afelimomab
Murine
F(ab’)2
TNF-α
Septic shock
Phase III
Abbott Laboratories
Enlimomab, BIRR-1
Murine
IgG2a
ICAM-1
Stroke
Phase II/III
Boehringer Ingelheim
ABX-CBL
Murine
IgG
Activated B and T cells, monocytes
Graft-versus-host disease
Phase III
Abgenix
TriGem
Murine
IgG
GD2 mimic
Malignant melanoma
Phase II
Titan
CeaVac
Murine
IgG
In combination with TriAb for NSCL (bivalent therapy)
CEA mimic
Colorectal cancer
Non–small-cell lung cancer (bivalent therapy with TriAb)
Phase III
Phase II
Titan
TriAb
Murine
IgG
In combination with CeaVac for NSCL (bivalent therapy)
HMFG mimic
Non–small-cell lung cancer (bivalent therapy with CeaVac)
Phase II
Phase II
Titan
MDX-210
Murine × Humanized
F(ab’)2
Bispecific
HER2/neu × CD64 (FcγRI)
HER-positive ovarian cancer
Phase III
Medarex, Immuno-Designed Molecules
MDX-220
Murine × Humanized
F(ab’)2
Bispecific
TAG-72 × CD64
Lung, colon, prostate, ovarian, endometrial, pancreatic, gastric cancers
Phase I/II
Immuno-Designed Molecules
MDX-44
Humanized
IgG
Immunotoxin
CD64
Psoriasis
Phase I/II
Medarex
MDX-101
Human
IgG1
CD152 (CTLA-4)
Prostate cancer, melanoma
Phase I/II
Medarex
Clinical trials with antibodies that are already approved as drugs in the United States (Table 1) are not included.
This primatized antibody contains variable domains from cynomolgus macaque (92% homology with human consensus sequence variable domains) and human IgG1 constant domains (184,185).
BLA, Biologics License Application; TNFα, tumor necrosis factor alpha; CEA, carcino embryonic antigen; VLA-4, very late antigen 4; IFN-γ, interferon gamma; FDA, Federal Drug Administration; EGFR, epidermal growth factor receptor; CA125, cancer antigen 125; HMFG, human milk fat globule; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; PEM, polymorphic epithelial mucin; EpCam, epithelial adhesion molecule; CD152, CTLA-4, cytotoxic T lymphocyte antigen 4; VEGF, vascular endothelial growth factor. Source: Refs. 1, 3, 179–185, company websites, www.BioSpace.com, and personal communications from Nilslonberg (Medarex Inc.) and Harold Keer (Titan Pharmaceuticals).