Next generation therapeutic mAb: Does Fc-engineering translate into clinical efficacy
Therapeutic monoclonal antibodies (mAb) represent the fastest growing group of biotherapeutics in recent years, both in the numbers of Abs entering clinical trials and in global sales revenue. The comparatively high approval success rates for mAbs may be one reason for the growing interest in the development of these therapeutics. mAbs are granted marketing approvals at twice the rate of small molecule drugs (approval success rates for the period 2005-2014 were somewhat lower for mAbs developed for cancer vs non-cancer indications - 21 vs 24%, respectively) (Kaplon et al., 2018).
Figure 1. Clinical phases for antibody therapeutics in development. Data as of November 2018. Totals include only antibody therapeutics sponsored by commercial firms; those sponsored solely by government, academic or non-profit organizations were excluded; biosimilars and Fc fusion proteins were excluded. Phase 1/2 included with Phase 2; late-stage studies include pivotal Phase 2, Phase 2/3 and Phase 3. Tables of mAbs in late-stage studies are available at www.antibodysociety.org. (Kaplon et al., 2018)
Therapeutic mAbs targeting cancer cells rely on two types of functionalities to achieve clinical efficacy:
direct induction of tumor cell apoptosis through blocking the binding of pro-survival ligands or inhibiting signal receptor dimerization and
immune-mediated effector functions via interaction of the crystalizable fragment (Fc) domain with receptors on various cell types such as antibody-dependent cellular cytotoxicity (ADCC), the activation of classical pathway of the complement system, and activation of the phagocytosis pathway (ADCP).
The strongest evidence for a role of Fc-mediated effector function in Ab-based cancer therapies came from clinical studies demonstrating an association between clinical responses and specific alloforms of activating hFcγRs: Single-nucleotide polymorphisms (SNPs) in FcγRIIA (H131R) and FcγRIIIA (V158F) have been associated with improved outcomes owing to a higher binding affinity to IgG1 and IgG2, which increases ADCC (Cartron et al., 2002; Musolino et al., 2008; Weng and Levy, 2003; Zhang et al., 2007).
More compelling, emerging preclinical data in mouse models demonstrate that also the activity of certain immune modulatory mAbs (such as anti-CTLA-4, -GITR, and -OX40) may extend beyond regulation of effector T cell responses and additionally relies upon ADCC to deplete regulatory T (Treg) cells (Bulliard et al., 2013, 2014; Selby et al., 2013; Simpson et al., 2013). Vargas et al., 2018 recently used huFcγRI mouse model to demonstrate that the Abs with improved FcγR binding profiles drove superior anti-tumor responses and survival. Further, FcγRI binding and cross-linking was shown to have a negative impact on the anti-PD-1 Ab-mediated anti-tumor activity (Zhang et al., 2018) and Fc engagement of innate immune cells by anti-PD-1 Ab has been suggested to be the underlying mechanism inducing tumor hyperprogression (Lo Russo et al., 2018). As the underlying mechanism of action Zhang et al., 2018 proposed that the cross-linking of PD-1 and FcγRI could reverse the function of anti-PD-1 Ab from blocking to activating.
In the light of the relevance of FcγR-mediated effects for therapeutic anti-cancer Abs and in particularly for the emerging second generation Ab preparations (with optimized FcγR binding profiles), including immune checkpoint targeting Abs it is essential to have model systems available that allow for the study of human IgG activity. Due to the differences between mouse and human FcγR-IgG interaction (discussed herein) the studies should be best conducted in the context of a human immune system in a pre-clinical setting in vivo.
The family of Fcγ receptors
Human FcγRs are divided into three types — FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD16). To decipher the role of FcγRs, results obtained in mouse model systems have been, and will continue to be, invaluable. Four different classes of FcγRs, known as FcγRI, FcγRIIB, FcγRIII and FcγRIV, have been recognized in mice. Based on the genomic localization and sequence similarity in the extracellular portion, mouse FcγRIV seems to be the orthologue of human FcγRIIIA, and mouse FcγRIII is most closely related to human FcγRIIA. However, differences in the intracellular domains and the cellular expression pattern of these receptors have to be taken into account when extrapolating data from animal studies to the human system and considering functional orthologous proteins corresponding to the mouse FcγRs.
Figure 2. The family of Fc receptors for IgG. Human and mouse Fc receptors for IgG (FcγRs) can be distinguished by their affinity for the antibody Fc-fragment and by the signalling pathways they induce.
FcγRs have traditionally been categorized according to:
their affinity for specific IgG subclasses; FcγRI (in humans and mice) and FcγRIV (mice only) were assigned as a high affinity receptors. FcγRI binds IgG2a in mice or IgG1 and IgG3 in human with an affinity of 10^8-10^9 M-1 and is constantly saturated with ligand (however cell activation only ensues after the receptors have been crosslinked by antigen). All other receptors have a 100–1000-fold lower affinity in the low to medium micromolar range and show a broader IgG subclass specificity. However, the classification of receptor affinity as ‘high’ or ‘low’ needs to be reconsidered given that the nature of the glycosylation pattern of either the antibody or the receptor affects the binding affinity for the different IgG.
the type of signalling pathway that they trigger; that is, whether it is inhibitory or activating. FcγRIIB is conserved in mice and humans and is the only known inhibitory FcγR; it transmits inhibitory signals through an immunoreceptor tyrosine-based inhibitory motif (ITIM) contained in its cytoplasmic region. All other receptors, with the exception of the human GPI-anchored FcγRIIIB, activate signalling pathways through ITAMs contained in their cytoplasmic regions.
The nature of the cell expressing a given FcR will determine a selection of biological activities. Cells can express the same receptor that will not trigger the same biological activities in each of the cell types. Besides, the expression of the various FcRs is strikingly different among hematopoietic cells. Innate immune effector cells, such as monocytes, macrophages, DCs, basophils and mast cells express activating and inhibitory FcγRs. T cells do not express FcγRs, B cells only express the inhibitory receptor FcγRIIB (FcγRIIB on B cells fnuctions as an important regulator of the activating signals transmitted by B cell receptor) and NK cells solely express the activating receptor FcγRIII. Though lack of inhibitory FcγR expression by NK cells suggests that these cells might be potent mediators of antibody-dependent cytotoxicity (ADCC) reactions, a growing body of experimental evidence in mouse model systems in vivo does not support this model.
Figure 3. Fcγ receptor (FcγR) expression on effector cells involved in cytotoxic, neutralizing, and agonistic antibody activity. Shown are the mouse and human immune cells and the expression of their respective FcγR repertoires (Jonsson and Daeron et al., 2012).
Major differences in receptor function and cellular expression pattern should be considered when evaluating human IgG activity.
Table 1 . Similarities and differences of human and murine FcγRs (Lux and Nimmerjahn, 2013).
Antibody-FcR interactions
The complexity in the FcγR family is mirrored by the presence of four different IgG subclasses in humans (IgG1-4) and mice (IgG1, IgG2a, IgG2b and IgG3). The Fc receptors binding IgGs are FcγR, FcRn and TRIM21. While the FcγR family binds ligands on the surface of the cells expressing them, FcRn and TRIM21 bind immunoglobulins once internalized.
The binding of IgG to FcγRs is a critical step for the initiation and control of cell-mediated effector functions, and each subclass of IgG exhibits a distinct profile of effector function, which is dictated by differential binding to each of the FcγRs. Human IgG1 and IgG3 are the most pro-inflammatory, however in mice IgG2a and IgG2b are the most pro-inflammatory IgG molecules and show greater activity than mouse IgG1 and IgG3 in many in vivo model systems.
Affinity of human IgG subclasses to mouse FcγR: The mouse FcγR display similar preference for human IgG as they do for mouse IgG, with FcγRI>> FcγRIV> FcγRIIb> FcγRIII (hIgG1 and hIgG3 mainly), which is close to what we know for the human ortholog receptors, hFcγRI>> hFcγRIIIa> FcγRIIa> FcγRIIb (where mFcgRIV is ortholog to hFcgRIIIa and mFcgRIII is ortholog to hFcgRIIa) (Dekkers et al., 2017).
High-affinity interactions with monomeric IgG2a are the hallmark of mouse FcγRI. In contrast, mouse FcγRIV has an intermediate affinity for mouse IgG2a and IgG2b. Of note, FcγRIV shows enhanced binding to defucosylated IgG. Mouse FcγRIII (CD16) is a low-affinity receptor that can bind to mouse IgG1, IgG2a, and IgG2b only in the form of immune complexes.
Figure 4. The human FcγR family contains orthologous receptors for mouse FcγRI (human FcγRIA), IIB (human FcγRIIB), III (human FcγRIIA), and IV (human FcγRIIIA) - based on the amino acid sequence of the extracellular domain - and can be distinguished by means of signal transduction and affinity for their respective ligands. Of note, certain human Fcγ-receptors, such as FcγRIIC and FcγRIIIB, do not exist in mice, and several of the human orthologues have nonverlapping functions compared to their mouse counterparts (Lux and Nimmerjahn, 2012).
There are several allelic variants of human FcγR genes that alter receptor function. Two common alleles of the FcgRIIIa gene encode two variants that differ at position 158, either a Val (V158) or a Phe (F158). Between the two variants, FcγRIIIA-V158 has a approximately 10-fold higher affinity to human IgG1, resulting in cells expressing the FcγRIIIA-V158 allele to mediate ADCC more effectively. Amino acid substitution in human FcγRIIA (histidine to arginine exchange at position 131) was shown to influence binding affinity to IgG in vitro and may impact therapeutic IgG activity.
Table 2 . Affinity of human IgG subclasses with mouse and human FcγRs (Lux and Nimmerjahn, 2012)
Antibody glycosylation
In addition to interactions between different amino acids, parts of the sugar moiety attached to N297 in the antibody Fc fragment also participate in this interaction. This sugar side chain consists of a conserved biantennary heptasaccharide core structure containing mannose and N‑ acetylglucosamine (GlcNac) with varying additions of terminal and branching residues such as fucose, GlcNac, galactose and sialic acid. Deletion of the whole sugar moiety changes the structure of the antibody Fc fragment resulting in greatly impaired binding to cellular FcγRs. Besides deglycosylated IgG, other more subtle variations in Ab glycosylation also have an impact on FcγR binding and activity.
The lack of fucose increases the affinity of all IgG subclasses to human activating cIIIA, and to its mouse orthologue FcγRIV, 10–50-fold, whereas binding to other human activating and inhibitory receptors, such as FcγRIIA or FcγRIIB, remains largely unchanged. As such, various strategies have focused on producing afucosylated antibodies to improve therapeutic efficacy.
Another residue in the sugar moiety of the antibody Fc fragment that has been implicated in affecting antibody activity is galactose. Depending on the absence or presence of galactose, IgG glycovariants are either called IgG‑G0 (no galactose) or IgG‑G1 or IgG-G2 variants, containing one or two galactose residues.
Antibody engineering
The intent is to reduce or to increase the effector function of FcγR-expressing cells, or to target more specifically a given FcγR by using a mutated IgG antibody, e.g. FcγRIIIA to favor ADCC or hFcRn to favor IgG half-life or transcytosis to tissues. For antibodies that target soluble molecules like cytokines or chemokines, or cell surface molecules, especially those on immune cells, abrogating effector functions is a necessity to prevent adverse reactions (e.g. cytokine storm, anaphylaxis, cell depletion). Conversely, for antibodies intended for oncology use, increasing effector functions, i.e. ADCC, CDC, ADP is desirable to increase their therapeutic activity.
In recombinant IgG therapeutics produced in Chinese hamster ovary (CHO) cells, the Fc N-glycans are heterogeneous biantennary complex type with a fucose residue attached to the core position. These N-glycans contain little to no sialic acid with zero (G0), one (G1) or two (G2) galactose residues.
Human IgG subclasses possess already inherently different abilities to bind complement C1q, hcs, hFcRn, hTRIM21, hFcRL5 (and hFcRL4?) and several mutations have been described that affect these interactions (for details see Bruhns and Jonsson, 2015).
While strategies in improving antibodies’ Fc affinity to selected FcγRs to improve immunotherapy of cancer is widely accepted, the concept of enhancing complement activation is still under debate and to our knowledge CDC-optimized antibody variants have not been tested in the clinic to date.
Figure 5. Top: Selected engineered IgG1-Fc variants with enhanced CDC activity. Bottom: IgG1 molecule with marked E345 position. Antibodies harboring amino acid exchanges at this (or other) positions are expressed as monomeric IgG molecules but form hexamers at the cell surface of target cells after antigen binding (Kellner et al., 2017).
Several approaches have been utilized to increase the affinity between Ab and the FcγRIII. These include engineering the Fc region through amino acid mutations and glycoengineering the Fc N-glycan to reduce core fucose (reviewed by Pereira et al., 2018):
It is now widely recognized that removal of the core fucose from Fc N-glycans represents an effective approach to enhance ADCC activity. Similarly, Fc galactosylation leads to increased FcgRIIIa binding, although to a significantly lesser extent compared to the removal of core fucose. Addition of galactose to afucosylated antibodies does not confer additional improvements to ADCC efficacy, indicating that afucosylation remains the major determinant of ADCC activity.
A series of engineered Fc variants of either single (S239D or I332E), double (S239D/I332E) or triple (S239D/I332E/A330L) mutations demonstrated up to 169-fold enhanced interaction with human FcgRIIIa and showed enhanced binding ratio between activating FcRgIIIa and inhibitory FcgRIIb of up to 9-fold.
Figure 6. Antibody model of a human IgG1 molecule engineered by exchanging selected amino acid positions. Yellow: amino acid substitutions introduced in Margetuximab (Macro-Genics). Purple: amino acid substitutions introduced in MOR208, Xmab-5574 (Xencor, MorphoSys) (Kellner et al., 2017).
Interestingly, there is no significant difference in ADCC activity mediated by core fucose removal or amino acid mutations S229D/D298A/I332E, and no additive effect was observed on B cell depletion activity of anti-CD20 IgG1 in human blood using a combination of these techniques.
Most common strategies employed to produce afucosylated Abs include
production in cell lines with modifications in biosynthetic enzymes: eg. production in CHO Lec13 cells (naturally deficient in GDP-mannose 4,6-dehydratase) resulting in a wide variety of fucosylation range (50-70% fucosylated Ab), or GDP-keto-6-deoxymannose 3,5-epimerase/4 reductase-knockout CHO for completely afucosylated Abs; production in YB2/0 cells with lower levels of Fut8 yielding Abs with lower levels of core fucose (EMABling platform), or FUT8-/- cell line for completely afucosylated Abs (Potelligent Technology, licenced by BioWa); generation of afucosylated Abs in CHO-gmt3 cells with inactivation of GDP-fucose transporter gene (Slc35c1); generation of bisecting GlcNac by overexpression of GnT-III in combination with a-mannosidase II (GlycoMab Technology, based on Roche Glycart AG's pioneering); GlycoExpress® expression platform consisting of a toolbox of glycoengineered cell lines optimized for producing biotherapeutics with desired glycan structures
biochemical inhibitors of fucosylation (2-fluorofucose, 5-alkynylfucose)
chemoenzymatic remodelling strategy by the use of an endo-b-N-acetylglucosamidase such as Endo S to remove the majority of N-glycans
alternative expression platforms
Table 3. Approaches to manipulate antibody fucosylation (Kellner et al., 2017).
Pereira et al., 2018 very recently summarized afucosylated Abs that have been studied in vivo in animal models and current status of the glycoengineered Abs in the clinics - there are currently 2 afucosylated antibodies on the market (obinutuzumab, GA101 or Gazyva; mogamulizumab, POTELIGEO) and 20 being evaluated in the clinical trials for cancer indications.
In contrast, the third approved Ab, atezolizumab, which targets PD-L1 and which is employed for immune checkpoint blockade by blocking interaction of PD-L1 with its inhibitory receptor PD-1 on T cells, contains an aglycosylated Fc domain and lacks Fc receptor and complement binding. This was achieved by replacing the N-glycosylation site asparagine 298 by alanine.
Table 4. Examples of Fc-engineered antibodies in advanced stages of clinical development (Kellner et al., 2017).
Assessing antibody effector functions: the need for humanized mouse models to study IgG activity in vivo
In vitro systems fail to recapitulate the diversity and specificity of Fc-FcγR interaction.
In vivo studies on individual IgG subclasses revealed that a restricted set of activating FcγRs is involved in mediating the activity. The only instance in which both the in vitro binding pattern and in vivo activity overlap is for mouse IgG1, which selectively binds FcγRIII. On the other hand, the activity of IgG2a is impaired in the presence of an FcγRIV blocking antibody in several model systems, but not in the absence of FcγRI and FcγRIII. These findings have some important implications with respect to the effector-cell types that are potentially responsible for these antibody activities in vivo: NK cells solely express FcγRIII and none of the other activating FcγRs. In FcγRIII knockout mice, in which NK cells are devoid of this activating FcγR the activity of IgG2a and IgG2b is not impaired, although FcγRIII can bind mouse IgG1, IgG2a and IgG2b with a similar low affinity in vitro. As mentioned before, though NK cells are widely believed to be the crucial mediators of ADCC reactions, in vivo evidence obtained in mouse model systems argues against a role for NK cells as the responsible effector cells in mice in vivo. Myeloid cells (granulocytes, monocytes or macrophages) have been suggested as the responsible cell types mediating IgG antibody activity in models of ADCC.
Implementing a model system that allows for the study of human IgG activity in the context of a human immune system in a pre-clinical setting in vivo presents several challenges. First, many antibodies directed against human target proteins do not recognize the mouse orthologous molecules. A solution to this problem is to generate transgenic mice expressing the human proteins regulated by their endogenous promoters. Humanization in the context of analyzing IgG effector functions can also be achieved by generating transgenic mice expressing human FcγRs. Since the human expression pattern is recapitulated on murine effector cells, these mice can be used to study the influence of FcγR, e.g., to test the efficacy of therapeutic IgG after transplantation of human tumor cells. Fully FcγR humanized mice have been generated by deleting all mouse activating FcγRs and crossing these mice to transgenic animals expressing all human FcγRs (Smith et al., 2012). The final step will be to further breed these animals to transgenic mice expressing the human target molecule of choice and ultimately to mice expressing human instead of mouse IgGs. Another possibility for humanizing mice for IgG research lies in the transfer of a human immune system (HIS; PBMCs, human hematopoietic CD34+ stem cells; characterized by the presence of all hematopoietic cell lineages), into immunodeficient mice. Ultimate solution would be to breed these animals to the common FcR γ-chain–deficient background, thus abrogating mouse FcγR function and allowing selective study of the interaction of human therapeutic IgGs with human effector cells (expressing human FcγRs) and human target cells within the human hematopoetic system in vivo.
HIS rodent models, which offer an improved in vivo system for translating Ab-based therapies to the clinic are being developed to support growing need from Biotech and Pharmaceutical companies to study aspects of Fc-mediated functions. Relevant models would be huNOG-EXL, NSG-SGM3, NRG mice and CIEA NOG, hIL-2 NOG, hIL-15 NOG mice. huNOG-EXL, NSG-SGM3 are HSC-engrafted mice with somewhat improved engraftment of the immune system compared to first generation humanized mice. CIEA NOG mouse is a super-immunodeficient model with human IL-2 transgene supporting the engraftment of human NK cells for ADCC studies. Further, two human cytokine-transgenic NOG models have been described to dramatically enhance NK cell differentiation from HSCs. Following HSC engraftment, hIL-2 NOG and hIL-15 NOG develop a human immune system that is nearly entirely NK cells.
Translational PK and Safety
The Fc region of therapeutic antibodies (Ab) can have an important role in their safety and/or efficacy and hence the various novel Ab modifications present new challenges in applying quantitative pharmacology and translational PK/PD.
Typically, systemically administered mAbs exhibit biphasic PK profiles in circulation (i.e., a relatively fast distribution phase followed by a slower elimination phase), confined distribution (in vasculature and interstitial space), long half-lives ( approx. 11–30 days in humans) from FcRn-mediated recycling, and nonlinear PK due to target-mediated clearance. While modulation of FcγR binding usually does not change PK profiles, engineered Abs with modified FcRn binding affinity demonstrate changes in mAb half-life. FcRn binds to the Fc region of the IgG in a pH-dependent manner and protects the internalized antibody from rapid intracellular catabolism - increased FcRn affinity results in longer serum half-life. A list of recently approved mAbs with their important PK parameters were reviewed by Ovacik and Lin, 2018.
As with pharmacology, the relevance of preclinical species deserves a special consideration for safety evaluation. Non-human primates (NHPs) are most frequently used species for selecting FIH dose due to their highly similar physiology to humans, similar FcRn binding affinity to human IgG and overall similarity in Ab disposition. It may still be necessary to characterize mAb PK in rodents if they are used to assess efficacy such as mouse xenograft models with human tumors.
Lessons from comparative clinical trials: Fc modifications do not translate into universal clinical benefit
Clinicians are now challenged with deciding whether to switch to next generation Ab formats in approved settings, accepting the potential for increased toxicity (for enhanced FcR engaging Abs) and probable increased cost. The decision of which Ab to employ should take into considerations the clinical context of Ab use, including differential benefit within histological subtypes or impact of host immune integrity.
It is still not clear whether antibody Fc engineering indeed translates into a higher therapeutic efficacy in patients. Detailed clinical comparisons between larger panels of protein-engineered and/or glyco-engineered Fc variants with distinct profiles of effector functions and corresponding non-engineered antibodies are missing. Such data may allow to unravel the relative contribution of selected effector cell populations to successful Ab therapy and to identify Fc variants with the highest potential in a given clinical application.
Whereas atezolizumab and mogamulizumab have not been compared to native antibodies with the same target antigen specificity, obinutuzumab was tested head-to-head against the native IgG1 CD20 antibody rituximab.
Obinutuzumab vs rituximab:
Obinutuzumab is a new generation non-fucosylated anti-CD20 antibody with “type II” properties (namely its ability to cause homotypic adhesion and employ a different mechanism of direct cell death) demonstrating superior activity in in vitro and preclinical studies when compared to rituximab and other “type I mAbs”.
Figure 7. Mechanism of action (MOA) of Rituximab (left) vs Obinutuzumab (right). Rituximab relocalizes CD20 to lipid rafts and appears to evoke minimal DCD but induces significant complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). In contrast, obinutuzumab does not induce CDC, but, by virtue of alternative binding to the CD20 molecule, can evoke greater DCD chiefly by mechanisms that are largely caspase-independent. The afucosylated Fc portion appears to confer more potent induction of ADCC and antibody-dependent phagocytosis (ADP) than rituximab. ADCC, antibody dependent cellular cytotoxicity, ADP, antibodydependent phagocytosis; CDC, complement dependent cytotoxicity; DCD, direct cell death; FCGR3A, Fcc receptor 3A (Freeman and Sehn, 2018).
The first direct comparison between rituximab and obinutuzumab was within a randomized phase II trial (GAUSS) involving 175 patients with relapsed indolent iNHL. Investigator-assessed ORR favoured obinutuzumab, 44.6% vs. 33.3% with a P-value of 0.08 and appeared to induce deeper remissions, with an almost two-fold higher complete response rate (CR+CRu 41.9% vs. 22.7%; P = 0.006). Although this trial was not powered to assess PFS, there was no apparent difference in PFS between the agents (Fig A). Improvements in progression-free survival (PFS) have been demonstrated in clinical trials comparing both antibodies head-to-head, both in patients with untreated symptomatic follicular lymphoma (FL) (GALLIUM trial, Fig. B) and treatment-naıve chronic lymphocytic leukaemia (CLL) and co-morbidities (CLL-11 trial, Fig. C - see ASCO Post 2018), however recent results from a large phase 3 trial involving patients with untreated diffuse large B cell lymphoma (DLBCL) demonstrated no advantage (Fig. D) (reviewed recently by Freeman and Sehn, 2018).
Figure 8. Outcome curves from comparative clinical trials. (A) PFS curve from GAUSS – no difference between obinutuzumab and rituximab monotherapy. (B) PFS curve from GALLIUM – statistically significant benefit with G-chemo arm compared with R-chemo. (C) PFS curve from CLL-11 (updated) – statistically significant benefit with G-Clb compared with R-CLB. (D) PFS curve from GOYA – no difference between G-CHOP and R-CHOP (Freeman and Sehn, 2018).
Obinutuzumab has exhibited a similar safety profile to rituximab, but in general has been associated with a higher incidence of adverse events. The incidence of severe IRRs (Grade ≥3) is at least double that observed for rituximab, some of which may relate to more pronounced cytokine release induced by this agent.
Based on the available evidence, obinutuzumab appears to offer an advantage over rituximab when combined with chlorambucil in patients with untreated CLL and co-morbidities that are unsuitable for fludarabine-based therapy. It has been approved and found to be cost-effective when compared to R-CLB in a number of countries. In symptomatic advanced-stage treatment na€ıve FL, both the EMA and the FDA have approved the use of obinutuzumab with chemotherapy followed by maintenance. Globally, the clinical benefits will need to be weighed against somewhat higher toxicity and additional cost. In the UK, combination was deemed insufficiently cost-effective by the National Institute of Clinical Excellence (NICE) to endorse its use in the upfront setting, at least at the present time.
Imgatuzumab vs cetuximab
Imgatuzumab (GA201) is a humanized engineered IgG1 anti-Epidermal Growth Factor Receptor (EGFR) mAb designed to enhance ADCC. In vitro binding of GA201 to EGFR inhibited EGF ligand binding, EGFR/HER2 heterodimerization, downstream signaling, and cell proliferation to a similar extent as cetuximab. However, GA201 exhibited superior binding to both the low- and high-affinity variants of FcγRIIIA. This resulted in significantly enhanced induction of ADCC compared with cetuximab against both KRAS-wild-type and -mutant tumor cells lines. Enhanced ADCC translated into superior in vivo efficacy in a series of mouse xenograft models suggesting that GA201 may be more effective than cetuximab in patients with EGFR+ solid tumors and may also represent a first-in-class treatment of patients with KRAS-mutated tumors.
To further investigate the PD of glycoengineered Ab, in an exploratory, multicenter trial randomized patients with operable HNSCC received two neoadjuvant infusions of imgatuzumab or cetuximab before surgical resection. While imgatuzumab demonstrated equal efficacy as cetuximab in terms of EGFR pathway inhibition and showed several indicators for an additional ADCC-enhancing effect of imgatuzumab based on the on-treatment dynamics of peripheral immune cells and cytokines (Temam et al., 2017).
Ultimately however, the enhanced ADCC activity did not translate into enhanced efficacy over cetuximab in a subsequent phase II trial: PFS was similar for the second-line imgatuzumab plus FOLFIRI versus cetuximab plus FOLFIRI in KRASwild-type metastatic colorectal cancer (Bridgewater at al., 2015).
