1394
`
`Discussion
`This study is the largest experience to date with the
`benzodiazepine antagonist flumazenil in the treatment of
`HE. The effects of the drug were assessed clinically and by
`SEP recordings. The late components of cortical SEPs
`(peaks N3 and P3) appear to be highly sensitive indicators of
`cortical dysfunction in HE.18 The results indicate that
`flumazenil may improve the HE that complicates both acute
`and chronic liver failure. Flumazenil treatment was
`associated with improvement in neurological status in 60%
`of episodes of HE; with one exception improvement
`occurred within a few minutes to an hour of drug
`administration. The speed of these responses contrasts with
`the interval of several hours that is typically necessary before
`HE improves after conventional therapies. The response to
`flumazenil in benzodiazepine intoxication is also very
`rapid. 19
`The 60% improvement rate may even underestimate the
`potential efficacy of flumazenil in the treatment of HE since
`most of the patients in this study had been encephalopathic
`for many days before flumazenil treatment and had not
`responded to conventional therapy. Furthermore all 5
`patients with clinical evidence of increased intracranial
`pressure due to brain oedema did not respond to flumazenil.
`1 of these patients improved after treatment with mannitol.
`The remaining 4 died within 3 days of flumazenil
`administration.
`In 8 of the 12 episodes reponding to flumazenil there was
`an exacerbation of HE 05-4 h after stopping treatment,
`This transient effect of the drug is consistent with its
`pharmacokinetics.2O,21 To achieve a sustained response
`continuous administration of the drug over longer periods
`may be necessary. Although these 12 episodes improved, no
`patient regained normal brain function at the end of
`treatment. The possibility that larger doses or a longer
`duration of treatment would have achieved complete
`improvement seems unlikely since, in benzodiazepine
`intoxication, much lower doses are sufficient for recovery.18
`In addition an increased GABA-ergic tone may be only one
`of many abnormalities of brain function in patients with
`liver failure and correction of this particular abnormality
`may therefore induce incomplete improvement.
`The mechanism by which flumazenil improves HE is
`uncertain. One possibility is displacement of an endogenous
`substance from the GABA -
`benzodiazepine-like
`benzodiazepine receptor. The presence of such a substance
`was suggested in the brains of animals with HE and in
`cerebrospinal fluid of patients dying with HE.22
`This study was supported by the Fonds zur Forderung der wissen-
`schaftlichen Forschung (P 6169 M). Flumazenil was provided by Hoffmann-
`La Roche, Basel, Switzerland.
`Correspondence should be addressed to G. G., lst Department of
`Medicine, University of Vienna, A-1090 Vienna, Austria.
`
`REFERENCES
`
`1. Schafer DF, Pappas SC, Brady LE, Jacobs R, Jones EA. Visual evoked potentials in a
`rabbit model of hepatic encephalopathy I: sequential changes and comparisons
`with drug induced comas. Gastroenterology 1984; 86: 540-45.
`2. Basile AS, Gammal SH, Mullen KD, Jones EA, Skolnick P. Differential
`responsiveness of cerebellar Purkinje neurons to GABA and benzodiazepine
`receptor ligands in an animal model of hepatic encephalopathy. J Neurosci 1988; 8:
`2414-21.
`3. Schafer DF, Jones EA. Hepatic encephalopathy and the &ggr;-aminobutyric-acid
`neurotransmitter system. Lancet 1982; ii: 18-20.
`4. Paul SM, Marangos PJ, Skolnick P. The benzodiazepine-GABA-chloride ionophore
`receptor complex: common site of minor tranquillizer action. Biol Psych 1981; 16:
`213-29.
`
`Preliminary Communication
`
`REMISSION INDUCTION IN NON-HODGKIN
`LYMPHOMA WITH RESHAPED HUMAN
`MONOCLONAL ANTIBODY CAMPATH-1H
`
`G. HALE1
`M. R. CLARK1
`R. MARCUS2
`G. WINTER3
`
`M. J. S. DYER2
`J. M. PHILLIPS1
`L. RIECHMANN3
`H. WALDMANN1
`
`Departments of Pathology1 and Haematology,2 University of
`Cambridge, and Laboratory of Molecular Biology,3 Cambridge
`
`Summary A genetically reshaped human IgG1
`monoclonal antibody (CAMPATH-1H)
`was used to treat two patients with non-Hodgkin
`lymphoma. Doses of 1-20 mg daily were given
`intravenously for up to 43 days. In both patients lymphoma
`cells were cleared from the blood and bone marrow and
`splenomegaly resolved. One patient had lymphadenopathy
`which also resolved. These effects were achieved without
`myelosuppression, and normal haemopoeisis was restored
`during the course of treatment, partially in one patient and
`completely in the other. No antiglobulin response was
`detected in either patient. CAMPATH-1H is a potent
`lympholytic antibody which might have an important use in
`the treatment of lymphoproliferative disorders and
`additionally as an immunosuppressive agent.
`
`5. Baraldi M, Zeneroli ML, Ventura E, et al. Supersensitivity of benzodiazepine
`receptors in hepatic encephalopathy due to fulminant hepatic failure in the rat:
`reversal by a benzodiazepine antagonist. Clin Sci 1984; 67: 167-75.
`6. Bassett ML, Mullen KD, Skolnick P, et al. Amelioration of hepatic encephalopathy by
`pharmacologic antagonism of the GABAA-benzodiazepine receptor complex in a
`rabbit model of fulminant hepatic failure. Gastroenterology 1987; 93: 1069-77
`7. Bansky G, Meier PJ, Ziegler WH, Walser H, Schmid M, Huber M. Reversal of
`hepatic coma by benzodiazepine antagonist (Ro 15-1788). Lancet 1985; i: 1324-25.
`8. Bansky G, Meier PJ, Riederer E, et al. Effect of a benzodiazepine antagonist in hepatic
`encephalopathy in man. Hepatology 1987; 7: 1103.
`9. Scollo-Lavizzari G, Steinmann E. Reversal of hepatic coma by benzodiazepine
`antagonist (Ro 15-1788). Lancet 1985; i: 1324.
`10. Burke DA, Mitchell KW, Al Mardini H, Record CO. Reversal of hepatic coma with
`flumazenil with improvement in visual evoked potentials. Lancet 1988; ii: 505-06.
`11. Sutherland LR, Minuk GY. Ro 15-1788 and hepatic failure. Ann Intern Med 1988,
`108: 158.
`12. Grimm G, Lenz K, Kleinberger G, et al. Ro 15-1788 improves coma in 4 out of 5
`patients with fulminant hepatic failure: verification by long latency auditory and
`somatosensory potentials. J Hepatol 1987; 4 (suppl 1): S21.
`13. Meier R, Gyr K. Treatment of hepatic encephalopathy (HE) with the benzodiazepine
`antagonist flumazenil: a pilot study. Eur J Anaesthesiol 1988; suppl 2: 139-46.
`14. Teasdale G, Jennett B. Assessment of coma and impaired consciousness: a practical
`scale. Lancet 1974; ii: 81-84.
`15. Conn HO, Lieberthal M. The hepatic coma syndromes and lactulose. Baltimore:
`Williams & Wilkins, 1979: 6.
`16. Cracco RQ, Bodis-Wolner I, eds. Frontiers of clinical neuroscience Vol 3: evoked
`potentials. New York. Alan R. Liss, 1986.
`17. Jasper HH. The ten/twenty electrode system of the International Federation.
`Electroencephologr Clin Neurophysiol 1958; 10: 371-75.
`18. Chu NS, Yang SS. Portal-systemic encephalopathy: alterations in somatosensory and
`brainstem auditory evoked potentials. J Neurol Sci 1988; 84: 41-50
`19. Prischl F, Donner A, Grimm G, et al. Value of flumazenil in benzodiazepine
`self-poisoning. Med Toxicol 1988; 3: 334-39.
`20. Lister R, Greenblatt D, Abemathy D, et al Pharmacokinetic studies on RO 15-1788, a
`benzodiazepine receptor ligand, in the brain of rat. Brain Res 1984; 290: 183-86.
`21. Roncardi G, Ziegler WH, Guentert TW. Pharmacokinetics of the new benzodiazepine
`antagonist Ro 15-1788 in man following intravenous and oral administration. Br J
`Clin Pharmacol 1986; 22: 421-28.
`22. Mullen KD, Martin JV, Mendelson WB, et al. Could an endogenous benzodiazepine
`ligand contribute to hepatic encephalopathy? Lancet 1988; i: 457-59.
`
`PFIZER and SAMSUNG v. GENENTECH
`IPR2017-01488
`PFIZER EX. 1207, Page 1
`
`

`

`1395
`
`Fig 1-Effect of CAMPATH-1G (A) and CAMPATH-1H (B) on blood counts in patient 1.
`A = lymphocytes; 6, = neutrophils.
`
`INTRODUCTION
`TUMOUR treatment by passive serotherapy has had a long
`and largely unsuccessful history. The advent of monoclonal
`antibodies gave fresh impetus to this approach, but results
`with unmodified antibodies are generally unremarkable.
`Efforts to enhance activity in vivo are now largely focused on
`the conjugation of antibodies to toxins or radionuclides.
`However, we are convinced that physiological effector
`mechanisms are still among the most potent and have tried
`to find the optimum combinations of antibody specificity
`and isotype to exploit them fully.
`One possible specificity is the CAMPATH-1 antigen.2 It
`does not readily undergo modulation and is abundantly
`expressed on virtually all lymphoid cells and monocytes, but
`not on other cell types.2,3 These properties make it a
`potential target for treatment of lymphoid malignant
`disorders and for immunosuppression. Several rat IgM and
`IgG antibodies to this antigen have been produced.4,5 The
`IgM (CAMPATH-1 M) is intensely lytic with human
`complement and is widely used for depletion of T cells from
`bone marrow to prevent graft-versus-host disease.6,7 The
`IgG2b (CAMPATH-lG) is the most potent for cell
`depletion in vivo,s probably because it binds to human Fc
`receptors and can activate the complement system.5 Patients
`with lymphoid malignant disorders treated with
`CAMPATH-1G (25-50 mg/day for 10 days) showed
`pronounced reduction in lymphoid infiltration of blood and
`bone marrow and improvement of splenomegaly.8
`However, treatment with rat antibody is likely to be limited
`by an antiglobulin response. This problem should be
`reduced or eliminated by use of a human antibody. A
`reshaped human antibody (CAMPATH-lH) has been
`constructed-the hypervariable regions of the rat antibody
`were transplanted into normal human immunoglobulin
`genes.9 Human IgG was chosen since it had greater activity
`than other human isotypes both in complement lysis and in
`cell-mediated killing.9-11
`Here we describe the use of CAMPATH-1H to treat two
`patients with non-Hodgkin lymphoma. Although it was
`possible to continue treatment for up to 6 weeks without the
`development of a neutralising antiglobulin response, the
`main point of this report is to describe the efficacy of the
`antibody in clearing large masses of tumour cells. This is the
`first report of treatment with a fully reshaped human
`monoclonal antibody.
`
`PATIENTS AND METHODS
`
`Approval for the use of monoclonal antibodies was given by the
`ethical committee of Addenbrooke’s Hospital and written consent
`was obtained from both patients.
`Antibodies were obtained from culture supernatant of cells
`growing in a hollow fibre bioreactor (’Acusyst-Jr’, Endotronics).
`CAMPATH-1G was purified by precipitation with ammonium
`affinity
`sulphate; CAMPATH-IH was purified
`by
`chromatography on protein-A-’Sepharose’. They were dissolved in
`phosphate-buffered saline, sterile filtered, and tested for pyrogen
`and sterility. Patients were prehydrated overnight and antibody,
`diluted in 500 ml saline, was infused over 2-4 h.
`CAMPATH-1 expression on tumour cells was measured by flow
`Serum
`complement-mediated
`lysis.2,3,8
`and
`cytometry
`of CAMPATH-1H were measured by
`concentrations
`immunofluorescence with normal lymphocytes.8 Southern blot
`analysis with an immunoglobulin JH probe was used to detect
`residual tumour cells in DNA extracted from mononuclear
`fractions of bone marrow.8 Antiglobulin responses were sought by
`two techniques. The first was a solid-phase enzyme-linked assay
`using microtitre plates coated with CAMPATH-1H. After
`incubation with patients’ serum samples, the assay was developed
`with biotin-labelled CAMPATH-1H followed by streptavidin-
`peroxidase. A mixture of monoclonal mouse antibodies against
`human IgG was used as a positive control and 500 ng/ml of this
`mixture could be detected. In the second assay, patients’ serum
`samples were mixed with red cells coupled with CAMPA TH -IH.12
`Agglutination by 5 ng/ml of the control mixture could be detected.
`Immunoglobulin allotypes were determined by means of standard
`reagents and techniques from the Central Laboratory of the
`Netherlands Red Cross blood transfusion service.
`
`Patient 1
`
`RESULTS
`
`A 69-year-old woman presented in 1983 with acute
`appendicitis. Massive splenomegaly was found (table) and
`the bone marrow was heavily infiltrated with lymphocytes,
`some of which had clefted nuclei and a single nucleolus.
`There was weak membrane expression of IgM-kappa.
`Computed tomography scan showed splenomegaly but no
`lymphadenopathy. Grade I, stage IVA non-Hodgkin
`lymphoma in leukaemic phase was diagnosed. Between
`1983 and 1987 the patient received oral and intravenous
`chemotherapy with combinations of cyclophosphamide,
`vincristine, prednisolone, and chlorambucil, which induced
`partial responses, the minimum level of marrow infiltration
`being 40%. Two courses of splenic radiotherapy were given,
`
`PFIZER and SAMSUNG v. GENENTECH
`IPR2017-01488
`PFIZER EX. 1207, Page 2
`
`

`

`1396
`
`but the second (in April 1987) was curtailed since the spleen
`grew larger during the course.
`In September 1987 the disease progressed with increases
`in blood lymphocytes (24 x 109 cells/1) and spleen size. The
`patient was treated with CAMPATH-1G for 8 days (fig
`lA). This treatment completely cleared lymphoma cells
`from blood and marrow but only partially reduced spleen
`size. CAMPATH-1 G induced fever, nausea, and vomiting,
`and the treatment was stopped on day 8 when it resulted in
`severe bronchospasm. (Such severe reactions have not been
`seen in twenty-one other patients who have received similar
`doses.) Reappearance of lymphoma cells in the blood was
`initially slow and the spleen size did not change for 5 months
`but there was little recovery of normal haemopoiesis. In
`March 1988 the patient began to lose weight and
`experienced drenching night sweats. The spleen enlarged
`and lymphoma cells reaccumulated in the blood. They
`had similar phenotype and identical rearranged
`immunoglobulin J H fragments to those seen before
`treatment. Marrow aspirate and trephine showed complete
`replacement of normal marrow by lymphoma cells (fig 2A);
`the patient became dependent on red-cell transfusions and
`was absolutely neutropenic.
`The patient’s serum did not block binding of
`CAMPATH-1H or CAMPATH-1G to
`normal
`lymphocytes and the tumour cells were still sensitive to these
`antibodies in vitro, so we decided to treat her with
`CAMPATH-1H. The starting dose was 1 mg daily and,
`since it was well tolerated, the dose was increased to a
`maximum of 20 mg/day, though the usual dose was 4
`mg/day owing to the small amount available. In all the
`patient received 126 mg over 30 days. The response was
`prompt; in 6 days the night sweats had abated, by day 10
`there was pronounced reduction in splenomegaly and
`recovery of blood neutrophils, and by day 18 lymphoma
`cells were cleared from the blood (fig IB). On day 28 a bone
`marrow aspirate and trephine were hypocellular but showed
`active myelopoiesis and erythropoiesis and no lymphoid
`cells (fig 2B). No CAMPATH-1-positive cells could be
`detected by flow cytometry. DNA from the mononuclear
`marrow cells was germline when probed with an
`immunoglobulin JH probe under conditions where clonal
`rearrangements could be detected in 0-2% of cells. Thus, we
`conclude that lymphoma cells were cleared from the
`marrow. The spleen volume was reduced about eight-fold
`(fig 3A, B), although it was still slightly larger than normal.
`Other than fever occurring about 1 h after the end of
`antibody infusions there were no adverse effects of antibody
`treatment until the 5th week, when severe rigors occurred
`after each infusion. No antiglobulin response could be
`detected and the rate of clearance of antibody from the
`serum was unchanged. For the next 3 weeks the patient
`continued to experience occasional fever and rigors. She was
`given oral cotrimoxazole because of her lymphopenia, but
`no infective cause of these symptoms could be found.
`In the next 4 months lymphocytes, which appeared
`morphologically normal, slowly reappeared in the blood (up
`to 0-2 x 109/1). They did not show the characteristic
`rearranged immunoglobulin fragments, and both CD3-
`positive and CD 19-positive cells were present (table).
`Serum immunoglobulin levels, which had been very low
`since presentation, have risen towards normal (table). A
`marrow aspirate and trephine taken 50 days after the end of
`treatment were again hypocellular but had no
`lymphomatous infiltration. This marrow sample contained
`
`PATIENT CHARACTERISTICS BEFORE AND AFTER TREATMENT
`WITH CAMPATH-IH
`
`*Made shortly after end of antibody treatment, except for lymphocyte
`phenotyping and serum immunoglobulins, which were assessed 6 weeks
`later.
`tBy computed tomography.
`ND = not done.
`
`4% CAMI’ATH-1-positive cells and showed some
`oligoclonal rearrangements of immunoglobulin genes.
`However, by day 100, lymphoma cells were again detected
`in the blood and the spleen size had started to increase. A
`second course of 12 days’ therapy with CAMPATH-1H
`was completed with similar therapeutic benefit to the first
`and no adverse effects. Since the main reservoir of disease in
`this patient appeared to be the spleen, splenectomy was
`carried out at the end of this second course of treatment. At
`that time no tumour cells could be detected in blood or
`marrow. The patient is now well 37 days after the
`splenectomy. The lymphocyte count is low but she has
`normal neutrophil, platelet, and red-cell counts.
`
`Patient 2
`
`A 67-year-old man presented in April 1988 with splenic
`pain; there was 12 cm splenomegaly, and computed
`tomography scan of thorax and abdomen revealed
`retrocrural and para-aortic lymphadenopathy, the largest
`node measuring 3 cm in diameter (fig 3C). A blood count
`revealed 36 6 x 109 lymphocytes/ml, the majority being
`lymphoplasmacytoid cells which expressed surface IgG-
`kappa and were characterised by large cytoplasmic periodic-
`acid-Schiff-positive vacuoles which could be intensely
`stained by anti-IgG. A marrow aspirate contained 72%
`(fig 2C). DNA from blood
`lymphomatous cells
`mononuclear cells showed biallelic rearrangement of
`immunoglobulin J genes but was germline with various
`T-cell receptor and oncogene probes. The lymphoma cells
`expressed the CAMPATH-1 I
`antigen in amounts
`comparable with normal lymphocytes but were more
`resistant to complement-mediated lysis. Stage IVA grade I
`
`PFIZER and SAMSUNG v. GENENTECH
`IPR2017-01488
`PFIZER EX. 1207, Page 3
`
`

`

`1397
`
`Fig 2-Cytology of bone marrow cells.
`A=patient 1 trephine before treatment with CAMPATH-1 H; B = patient 1 trephine on day 43 (ie, 16 days after treatment); C = patient 2 aspirate before
`treatment with CAMPATH-1H; D =patient 2 aspirate on day 78 (ie, 35 days after treatment). Reduced by 58% from x 100 (A,B), x 1000 (C), x 400 (D).
`
`Fig 3-Computed tomography scans showing affected spleens and lymphnode.
`A=patient 1 before treatment with CAMPATH-1H; B=patient 1 on day 57; C=patient 2 before treatment with CAMPATH-1H (retrocrural node
`arrowed); D = patient 2 on day 51.
`
`PFIZER and SAMSUNG v. GENENTECH
`IPR2017-01488
`PFIZER EX. 1207, Page 4
`
`

`

`1398
`
`Fig 4-Effect of CAMPATH-1H on blood counts in patient 2.
`A = lymphocytes, A = neutrophils.
`
`lymphoplasmacytoid non-Hodgkin lymphoma was
`diagnosed.
`The patient was offered CAMPATH-1H as primary
`therapy and received a total of 85 mg over 43 days. This
`resulted in clearance of the lymphoma cells and normal
`lymphocytes from blood (fig 4) and marrow (fig 2D),
`resolution of splenomegaly, and improvement in the
`lymphadenopathy. A computed tomography scan taken 8
`days after the end of antibody treatment was normal (fig
`3D). A bone marrow aspirate taken at the same time showed
`active haemopoiesis but no lymphoma cells, and no
`CAMPATH-1-positive cells could be detected by flow
`cytometry. DNA from the mononuclear fraction of this
`marrow showed only germline configuration when probed
`with the immunoglobulin J H probe. By day 78
`morphologically normal blood lymphocytes began to
`reappear and none of the vacuolated cells could be seen. The
`patient remains well and off therapy.
`Some toxic effects of CAMPATH-1H were observed.
`The first dose was stopped after 3 mg had been given
`because of hypotension, possibly caused by tumour lysis.
`This problem was subsequently avoided by giving smaller
`doses at a slower rate and when lymphoma cells had been
`cleared from the blood, the dose was increased to a
`maximum of 8 mg over 4 h without any effect on blood
`pressure. Nevertheless, all doses induced fever (up to
`38-5°C), and malaise for up to 36 h, but these were not severe
`enough to stop antibody treatment which, after the first
`week, was given on an outpatient basis. Treatment was
`stopped after 43 days because of the development of an
`urticarial rash after two successive antibody infusions.
`
`Half-life of CAMPA TH-LH
`The concentration of CAMPATH-1H was measured in
`serum samples taken before and after antibody infusions and
`at other times throughout treatment. In theory, a dose of 4-6
`mg corresponds to about 1 Jlg/ml in the plasma. In fact we
`could not detect free antibody till day 4-6, presumably
`because of rapid uptake by the tumour mass. After that, the
`rate of clearance was roughly constant, with the
`concentration being about 30-70% of the theoretical level
`
`immediately after infusion and about 5-20% after 24 h. The
`rate of clearance of CAMPATH-1H was possibly slightly
`slower than that of the rat CAMPATH-1 G, but still much
`faster than that of normal human IgGl .13
`
`Lack of Antiglobulin Response
`The allotype ofCAMPATH-lH is Glm(1,2,17),Km(3).
`Patient 1 was Glm(1,3,17),Km(3) and patient 2 was
`Glm(3),Km(3), so both could theoretically have made an
`anti-allotype response as well as a response to the
`hypervariable regions. However, we failed to detect any
`antiglobulin to CAMPATH-1H either by the solid-phase
`enzyme-linked assay or by the more sensitive
`haemagglutination assay. In addition, the rate of clearance of
`CAMPATH-1H did not change and free antibody could be
`detected for up to 8 days after the last dose had been given. It
`is possible that the reactions experienced at the end of the
`course of treatment could have been provoked by
`contaminating non-human proteins in the antibody
`preparation.
`
`,
`
`DISCUSSION
`The remissions achieved in these two patients show that it
`is possible to clear large numbers of tumour cells with small
`amounts of an unmodified monoclonal antibody. The
`effects in the first patient were far superior to the results of
`previous chemotherapy and radiotherapy. The selective
`lysis of lymphoma cells with recovery of normal
`haemopoiesis during the course of treatment was an
`important advantage, which allowed treatment to be given
`largely on an outpatient basis. We believe the choice of
`antibody specificity and isotype is important; indeed, it may
`be why we had more success than previous efforts with other
`monoclonal antibodies. 1116 The CAMPATH-1 antigen
`seems to be a good target because it is widely distributed and
`abundant, and does not suffer from antigenic
`modulation .2,3,11,17 This study shows that, as predicted,
`human IgGl can bring about cell lysis in vivo, though we
`cannot yet assess the relative importance of humoral or
`cellular mechanisms. There was no change in serum
`complement levels (CH50, C3, or C4 components) during
`antibody treatment (data not shown), but this does not
`exclude a role for C3 in cell clearance.
`Although the two patients did not make any serologically
`detectable antiglobulin response, it would be premature to
`draw general conclusions about the immunogenicity of
`human monoclonal antibodies, since CAMPATH-1H itself
`is probably immunosuppressive and the patients were
`already immunosuppressed as a result of their disease.
`Nevertheless, it was encouraging that two courses of
`antibody treatment could be given, even in the patient who
`had previously had unusually severe reactions to the original
`rat antibody.
`The long-term benefit of treatment with CAMPATH-
`1H can only be assessed in a much larger trial when it would
`probably be combined with more conventional
`chemotherapy and radiotherapy. It may have wider
`applications as an immunosuppressive agent for
`transplantation and possibly autoimmune disease, since we
`already know that the rat antibody CAMPATH-1 G is a
`potent immunosuppressant in the short-term.
`We thank the patients and families, nursing staff, medical colleagues, and
`Prof F. G. J. Hayhoe for their cooperation, encouragement and support; and
`Dr D. Gilmore, Dr H. S. Kruger-Gray, Prof R. R. A. Coombs, Mark
`
`PFIZER and SAMSUNG v. GENENTECH
`IPR2017-01488
`PFIZER EX. 1207, Page 5
`
`

`

`Frewin, and Caroline McHarg for their help. This work was supported by the
`Medical Research Council, Wellcome Biotech Ltd, and St John’s College
`Cambridge (Meres studentship to M. J. S. D.). ’CAMPATH’ is a trade mark
`of Well come Foundation.
`
`Correspondence should be addressed to H. W., Department of Pathology,
`University of Cambridge, Tennis Court Road, Cambridge CB2 1QP.
`
`REFERENCES
`
`1. Currie GA. Eighty years of immunotherapy: a review of immunological methods used
`for treatment of human cancer. Br J Cancer 1972; 26: 141-53.
`2. Hale G, Bright S, Chumbley G, et al Removal of T cell from bone marrow for
`transplantation: a monoclonal antilymphocyte antibody that fixes human
`complement. Blood 1983; 62: 873-82.
`3. Hale G, Swirsky D, Waldmann H, Chan LC. Reactivity of rat monoclonal antibody
`CAMPATH-1 with human leukaemia cells and its possible application for
`autologous bone marrow transplantation . Br J Haematol 1985; 60: 41-48.
`4. Hale G, Hoang T, Prospero T, Watt SM, Waldmann H. Removal of T cells from bone
`marrow for transplantation: comparison of rat monoclonal anti-lymphocyte
`antibodies of different isotypes. Mol Biol Med 1983; 1: 305-19.
`5. Hale G, Cobbold SP, Waldmann H, Easter G, Matejtschuk P, Coombs RRA.
`Isolation of low-frequency class-switch variants from rat hybrid myelomas.
`J Immunol Meth 1987; 103: 59-67.
`
`1399
`
`6. Waldmann H, Or R, Hale G, et al. Elimination of graft-versus-host disease by in vitro
`depletion of alloreactive lymphocytes using a monoclonal rat anti-human
`lymphocyte antibody (CAMPATH-1). Lancet 1984; ii: 483.
`7. Hale G, Cobbold S, Waldmann H. T-cell depletion with CAMPATH-1 in allogeneic
`bone marrow transplantation. Transplantation 1988; 45: 753-59.
`8. Dyer MJS, Hale G, Hayhoe FGJ, Waldmann H. Effects of CAMPATH-1 antibodies
`in vivo m patients with lymphoid malignancies: influence of antibody isotype.
`Blood (in press).
`9. Riechmann L, Clark MR, Waldmann H, Winter G. Reshaping human antibodies for
`therapy. Nature 1988; 332: 323-27
`10. Bruggemann M, Williams GT, Bindon CI, et al. Comparison of the effector functions
`of human immunoglobulins using a matched set of chimeric antibodies. J Exp Med
`1987; 166: 1351-61.
`11. Bindon CI, Hale G, Bruggemann M, Waldmann H. Human monoclonal IgG
`antibodies differ in complement activation function at the level of C4 as well as C1q.
`J Exp Med 1988; 268: 127-52.
`12. Hale G, Swirsky DM, Hayhoe FGJ, Waldmann H. Effects of monoclonal
`anti-lymphocyte antibodies in vivo in monkeys and human. Mol Biol Med 1983; 1:
`321-24.
`13. Morell A, Terry WD, Waldmann TA. Metabolic properties of IgG subclasses in man.
`J Clin Invest 1970; 49: 673.
`14. Ritz J, Schlossman SF. Utilization of monoclonal antibodies in the treatment of
`leukemia and lymphoma. Blood 1982; 59: 1-11.
`15. Levy R, Miller RA. Biological and clinical implications of lymphocyte hybridomas:
`tumor therapy with monoclonal antibodies. Annu Rev Med 1983; 34: 107-16.
`16. Stevenson GT, Glennie MJ. Surface immunoglobulin of B-lymphocyte tumours as a
`therapeutic target. Cancer Surv 1985; 4: 213-44.
`17. Bindon Ci, Hale G, Waldmann H. Importance of antigen specificity for complement
`mediated lysis by monoclonal antibodies. Eur J Immunol (in press).
`
`Reviews of Books
`
`Worse than the Disease: Pitfalls of Medical
`Progress
`Diana B. Dutton with contributions by Thomas A. Preston and
`Nancy E. Pfund. Cambridge: Cambridge University Press.
`1988. Pp 528. /:25. ISBN 0-521340233.
`Dr Dutton is a sociologist with a special interest in the
`development of health policy. She clearly shares Lord
`Salisbury’s view that doctors are a variety of expert who
`require to have their strong wine diluted by very large
`admixture of insipid commonsense. On the evidence of this
`book she has a strong case. Four detailed histories of major
`medical developments are presented. Two of these
`initiatives caused considerable harm and suffering to a small
`number of people at enormous cost and without clinical
`benefit. The American swine flu mass immunisation
`programme was designed to protect against an epidemic that
`did not occur and resulted in severe neurological disease in
`some unlucky recipients. The artificial heart programme
`consumed vast federal funds over many years and, when
`tested (probably prematurely) in man, failed to extend life
`significantly but afforded a few individuals a miserable
`death. A third development, diethylstilboestrol, was hailed
`as a wonder drug and widely put to unproven use until
`serious adverse sequelae were noted in the children of
`women who had received it. In the fourth case history, the
`development of recombinant DNA methods, there is no
`discernible evidence of physical harm, although the
`safeguards introduced in the early days, after public debate,
`were brushed aside under commercial and scientific
`pressures. In the absence of any harmful outcome, this last
`case is very much the odd man out; I suspect that it is
`included because of the early public consultation, although
`this consultation had little effect upon the course of
`events.
`In the first three examples there is an element of being
`wise after the event. At least some of those involved acted
`from the purest of motives when there was considerable
`
`uncertainty about the paths to be taken. Later, market forces
`distorted clinical and scientific judgment, precipitating
`unjustified clinical use together with obstruction of
`necessary action by the regulatory authorities. It is a sorry
`tale, and if there is one obvious lesson it is that the
`marketplace is no testing ground for medical innovation of
`the sort discussed here. Where financial returns are
`involved, they only too easily corrupt scientific, clinical, and
`ethical judgment-in ways that are not always obvious to the
`participants at the time.
`Dutton continues to swim against the tide by suggesting
`that governments must take responsibility for safeguarding
`society from the consequences of regarding medical
`developments as saleable commodities. This philosophy she
`sees as a variant of Tudor Hart’s inverse-care law whereby
`the areas of greatest need attract the least resources. The
`difficulty here is obvious from one of her case histories-the
`mass immunisation programme against swine influenza.
`Here an early warning system was triggered too easily, a
`President in an election year needed to present a decisive
`image, and experts lost the courage of their convictions in
`the face of the high cost of possibly being proved wrong. The
`result was a programme that would have failed to stem an
`epidemic even if the epidemic had occurred. Where
`powerful governmental machinery existed it over-reacted in
`an incompetent way.
`Dutton recognises the shortcomings of governmental
`machinery. Her solution is public accountability through
`other mechanisms at local and national level. She
`recognises the obvious difficulty presented by the way the
`popular voice is heard at present. This heavenly chorus
`"sings with a strong upper class accent. Probably about 90%
`of the people cannot get into the pressure system". One
`model she sees in a favourable light is the citizens’ panel set
`up by the Cambridge (Massachusetts) City Manager to
`examine the potential risks of recombinant DNA research at
`two of the world’s leading universities. This unique
`approach employed non-experts as a jury. At a national level
`she proposes greater congressional oversight of medical
`innovation and perhaps the construction of an overall
`policy-making body within the United States Department
`
`PFIZER and SAMSUNG v. GENENTECH
`IPR2017-01488
`PFIZER EX. 1207, Page 6
`
`